Substituted [1,2,4]triazolo[1,5-a]pyrazines as LSD1 inhibitors

ABSTRACT

The present invention is directed to [1,2,4]triazolo[1,5-a]pyridine and [1,2,4]triazolo[1,5-a]pyrazine derivatives of Formula IIa, or a pharmaceutically acceptable salt thereof, which are LSD1 inhibitors useful in the treatment of diseases such as cancer.

FIELD OF THE INVENTION

The present invention is directed to [1,2,4]triazolo[1,5-a]pyridine and[1,2,4]triazolo[1,5-a]pyrazine derivatives which are LSD1 inhibitorsuseful in the treatment of diseases such as cancer.

BACKGROUND OF THE INVENTION

Epigenetic modifications can impact genetic variation but, whendysregulated, can also contribute to the development of various diseases(Portela, A. and M. Esteller, Epigenetic modifications and humandisease. Nat Biotechnol, 2010. 28(10): p. 1057-68; Lund, A. H. and M.van Lohuizen, Epigenetics and cancer. Genes Dev, 2004. 18(19): p.2315-35). Recently, in depth cancer genomics studies have discoveredmany epigenetic regulatory genes are often mutated or their ownexpression is abnormal in a variety of cancers (Dawson, M. A. and T.Kouzarides, Cancer epigenetics: from mechanism to therapy. Cell, 2012.150(1): p. 12-27; Waldmann, T. and R. Schneider, Targeting histonemodifications—epigenetics in cancer. Curr Opin Cell Biol, 2013. 25(2):p. 184-9; Shen, H. and P. W. Laird, Interplay between the cancer genomeand epigenome. Cell, 2013. 153(1): p. 38-55). This implies epigeneticregulators function as cancer drivers or are permissive fortumorigenesis or disease progression. Therefore, deregulated epigeneticregulators are attractive therapeutic targets.

One particular enzyme which is associated with human diseases is lysinespecific demethylase-1 (LSD1), the first discovered histone demethylase(Shi, Y., et al., Histone demethylation mediated by the nuclear amineoxidase homolog LSD1. Cell, 2004. 119(7): p. 941-53). It consists ofthree major domains: the N-terminal SWIRM which functions in nucleosometargeting, the tower domain which is involved in protein-proteininteraction, such as transcriptional co-repressor, co-repressor ofRE1-silencing transcription factor (CoREST), and lastly the C terminalcatalytic domain whose sequence and structure share homology with theflavin adenine dinucleotide (FAD)-dependent monoamine oxidases (i.e.,MAO-A and MAO-B) (Forneris, F., et al., Structural basis of LSD1-CoRESTselectivity in histone H3 recognition. J Biol Chem, 2007. 282(28): p.20070-4; Anand, R. and R. Marmorstein, Structure and mechanism oflysine-specific demethylase enzymes. J Biol Chem, 2007. 282(49): p.35425-9; Stavropoulos, P., G. Blobel, and A. Hoelz, Crystal structureand mechanism of human lysine-specific demethylase-1. Nat Struct MolBiol, 2006. 13(7): p. 626-32; Chen, Y., et al., Crystal structure ofhuman histone lysine-specific demethylase 1 (LSD1). Proc Natl Acad SciUSA, 2006. 103(38): p. 13956-61). LSD1 also shares a fair degree ofhomology with another lysine specific demethylase (LSD2) (Karytinos, A.,et al., A novel mammalian flavin-dependent histone demethylase. J BiolChem, 2009. 284(26): p. 17775-82). Although the biochemical mechanism ofaction is conserved in two isoforms, the substrate specificities arethought to be distinct with relatively small overlap. The enzymaticreactions of LSD1 and LSD2 are dependent on the redox process of FAD andthe requirement of a protonated nitrogen in the methylated lysine isthought to limit the activity of LSD1/2 to mono- and di-methylatedlysines at the position of 4 or 9 of histone 3 (H3K4 or H3K9). Thesemechanisms make LSD1/2 distinct from other histone demethylase families(i.e. Jumonji domain containing family) that can demethylate mono-, di-,and tri-methylated lysines through alpha-ketoglutarate dependentreactions (Kooistra, S. M. and K. Helin, Molecular mechanisms andpotential functions of histone demethylases. Nat Rev Mol Cell Biol,2012. 13(5): p. 297-311; Mosammaparast, N. and Y. Shi, Reversal ofhistone methylation: biochemical and molecular mechanisms of histonedemethylases. Annu Rev Biochem, 2010. 79: p. 155-79).

Methylated histone marks on H3K4 and H3K9 are generally coupled withtranscriptional activation and repression, respectively. As part ofcorepressor complexes (e.g., CoREST), LSD1 has been reported todemethylate H3K4 and repress transcription, whereas LSD1, in nuclearhormone receptor complex (e.g., androgen receptor), may demethylate H3K9to activate gene expression (Metzger, E., et al., LSD1 demethylatesrepressive histone marks to promote androgen-receptor-dependenttranscription. Nature, 2005. 437(7057): p. 436-9; Kahl, P., et al.,Androgen receptor coactivators lysine-specific histone demethylase 1 andfour and a half LIM domain protein 2 predict risk of prostate cancerrecurrence. Cancer Res, 2006. 66(23): p. 11341-7). This suggests thesubstrate specificity of LSD1 can be determined by associated factors,thereby regulating alternative gene expressions in a context dependentmanner. In addition to histone proteins, LSD1 may demethylatenon-histone proteins. These include p53 (Huang, J., et al., p53 isregulated by the lysine demethylase LSD1. Nature, 2007. 449(7158): p.105-8.), E2F (Kontaki, H. and I. Talianidis, Lysine methylationregulates E2F1-induced cell death. Mol Cell, 2010. 39(1): p. 152-60,STAT3 (Yang, J., et al., Reversible methylation of promoter-bound STAT3by histone-modifying enzymes. Proc Natl Acad Sci USA, 2010. 107(50): p.21499-504), Tat (Sakane, N., et al., Activation of HIV transcription bythe viral Tat protein requires a demethylation step mediated bylysine-specific demethylase 1 (LSD1/KDM1). PLoS Pathog, 2011. 7(8): p.e1002184), and myosin phosphatase target subunit 1 (MYPT1) (Cho, H. S.,et al., Demethylation of RB regulator MYPT1 by histone demethylase LSD1promotes cell cycle progression in cancer cells. Cancer Res, 2011.71(3): p. 655-60). The lists of non-histone substrates are growing withtechnical advances in functional proteomics studies. These suggestadditional oncogenic roles of LSD1 beyond regulating chromatinremodeling. LSD1 also associates with other epigenetic regulators, suchas DNA methyltransferase 1 (DNMT1) (Wang, J., et al., The lysinedemethylase LSD1 (KDM1) is required for maintenance of global DNAmethylation. Nat Genet, 2009. 41(1): p. 125-9) and histone deacetylases(HDACs) complexes (Hakimi, M. A., et al., A core-BRAF35 complexcontaining histone deacetylase mediates repression of neuronal-specificgenes. Proc Natl Acad Sci USA, 2002. 99(11): p. 7420-5; Lee, M. G., etal., Functional interplay between histone demethylase and deacetylaseenzymes. Mol Cell Biol, 2006. 26(17): p. 6395-402; You, A., et al.,CoREST is an integral component of the CoREST-human histone deacetylasecomplex. Proc Natl Acad Sci USA, 2001. 98(4): p. 1454-8). Theseassociations augment the activities of DNIVIT or HDACs. LSD1 inhibitorsmay therefore potentiate the effects of HDAC or DNIVIT inhibitors.Indeed, preclinical studies have shown such potential already (Singh, M.M., et al., Inhibition of LSD1 sensitizes glioblastoma cells to histonedeacetylase inhibitors. Neuro Oncol, 2011. 13(8): p. 894-903; Han, H.,et al., Synergistic re-activation of epigenetically silenced genes bycombinatorial inhibition of DNMTs and LSD1 in cancer cells. PLoS One,2013. 8(9): p. e75136).

LSD1 has been reported to contribute to a variety of biologicalprocesses, including cell proliferation, epithelial-mesenchymaltransition (EMT), and stem cell biology (both embryonic stem cells andcancer stem cells) or self-renewal and cellular transformation ofsomatic cells (Chen, Y., et al., Lysine-specific histone demethylase 1(LSD1): A potential molecular target for tumor therapy. Crit RevEukaryot Gene Expr, 2012. 22(1): p. 53-9; Sun, G., et al., Histonedemethylase LSD1 regulates neural stem cell proliferation. Mol CellBiol, 2010. 30(8): p. 1997-2005; Adamo, A., M. J. Barrero, and J. C.Izpisua Belmonte, LSD1 and pluripotency: a new player in the network.Cell Cycle, 2011. 10(19): p. 3215-6; Adamo, A., et al., LSDregulates thebalance between self-renewal and differentiation in human embryonic stemcells. Nat Cell Biol, 2011. 13(6): p. 652-9). In particular, cancer stemcells or cancer initiating cells have some pluripotent stem cellproperties that contribute to the heterogeneity of cancer cells. Thisfeature may render cancer cells more resistant to conventionaltherapies, such as chemotherapy or radiotherapy, and then developrecurrence after treatment (Clevers, H., The cancer stem cell: premises,promises and challenges. Nat Med, 2011. 17(3): p. 313-9; Beck, B. and C.Blanpain, Unravelling cancer stem cell potential. Nat Rev Cancer, 2013.13(10): p. 727-38). LSD1 was reported to maintain an undifferentiatedtumor initiating or cancer stem cell phenotype in a spectrum of cancers(Zhang, X., et al., Pluripotent Stem Cell Protein Sox2 ConfersSensitivity to LSD1 Inhibition in Cancer Cells. Cell Rep, 2013. 5(2): p.445-57; Wang, J., et al., Novel histone demethylase LSD1 inhibitorsselectively target cancer cells with pluripotent stem cell properties.Cancer Res, 2011. 71(23): p. 7238-49). Acute myeloid leukemias (AMLs)are an example of neoplastic cells that retain some of their lessdifferentiated stem cell like phenotype or leukemia stem cell (LSC)potential. Analysis of AML cells including gene expression arrays andchromatin immunoprecipitation with next generation sequencing (ChIP-Seq)revealed that LSD1 may regulate a subset of genes involved in multipleoncogenic programs to maintain LSC (Harris, W. J., et al., The histonedemethylase KDMJA sustains the oncogenic potential of MLL-AF9 leukemiastem cells. Cancer Cell, 2012. 21(4): p. 473-87; Schenk, T., et al.,Inhibition of the LSD1 (KDMJA) demethylase reactivates theall-trans-retinoic acid differentiation pathway in acute myeloidleukemia. Nat Med, 2012. 18(4): p. 605-11). These findings suggestpotential therapeutic benefit of LSD1 inhibitors targeting cancershaving stem cell properties, such as AMLs.

Overexpression of LSD1 is frequently observed in many types of cancers,including bladder cancer, NSCLC, breast carcinomas, ovary cancer,glioma, colorectal cancer, sarcoma including chondrosarcoma, Ewing'ssarcoma, osteosarcoma, and rhabdomyosarcoma, neuroblastoma, prostatecancer, esophageal squamous cell carcinoma, and papillary thyroidcarcinoma. Notably, studies found over-expression of LSD1 wassignificantly associated with clinically aggressive cancers, forexample, recurrent prostate cancer, NSCLC, glioma, breast, colon cancer,ovary cancer, esophageal squamous cell carcinoma, and neuroblastoma. Inthese studies, either knockdown of LSD1 expression or treatment withsmall molecular inhibitors of LSD1 resulted in dec reased cancer cellproliferation and/or induction of apoptosis. See, e.g., Hayami, S., etal., Overexpression of LSD1 contributes to human carcinogenesis throughchromatin regulation in various cancers. Int J Cancer, 2011. 128(3): p.574-86; Lv, T., et al., Over-expression of LSD1 promotes proliferation,migration and invasion in non-small cell lung cancer. PLoS One, 2012.7(4): p. e35065; Serce, N., et al., Elevated expression of LSD1(Lysine-specific demethylase 1) during tumour progression frompre-invasive to invasive ductal carcinoma of the breast. BMC ClinPathol, 2012. 12: p. 13; Lim, S., et al., Lysine-specific demethylase 1(LSD1) is highly expressed in ER-negative breast cancers and a biomarkerpredicting aggressive biology. Carcinogenesis, 2010. 31(3): p. 512-20;Konovalov, S. and I. Garcia-Bassets, Analysis of the levels oflysine-specific demethylase 1 (LSD1) mRNA in human ovarian tumors andthe effects of chemical LSD1 inhibitors in ovarian cancer cell lines. JOvarian Res, 2013. 6(1): p. 75; Sareddy, G. R., et al., KDM1 is a noveltherapeutic target for the treatment of gliomas. Oncotarget, 2013. 4(1):p. 18-28; Ding, J., et al., LSD1-mediated epigenetic modificationcontributes to proliferation and metastasis of colon cancer. Br JCancer, 2013. 109(4): p. 994-1003; Bennani-Baiti, I. M., et al.,Lysine-specific demethylase 1 (LSD1/KDM1A/AOF2/BHC110) is expressed andis an epigenetic drug target in chondrosarcoma, Ewing's sarcoma,osteosarcoma, and rhabdomyosarcoma. Hum Pathol, 2012. 43(8): p. 1300-7;Schulte, J. H., et al., Lysine-pecific demethylase 1 is stronglyexpressed in poorly differentiated neuroblastoma: implications fortherapy. Cancer Res, 2009. 69(5): p. 2065-71; Crea, F., et al., Theemerging role of histone lysine demethylases in prostate cancer. MolCancer, 2012. 11: p. 52; Suikki, H. E., et al., Genetic alterations andchanges in expression of histone demethylases in prostate cancer.Prostate, 2010. 70(8): p. 889-98; Yu, Y., et al., High expression oflysine-specific demethylase 1 correlates with poor prognosis of patientswith esophageal squamous cell carcinoma. Biochem Biophys Res Commun,2013. 437(2): p. 192-8; Kong, L., et al., Immunohistochemical expressionof RBP2 and LSD1 in papillary thyroid carcinoma. Rom J Morphol Embryol,2013. 54(3): p. 499-503.

Recently, the induction of CD86 expression by inhibiting LSD1 activitywas reported (Lynch, J. T., et al., CD86 expression as a surrogatecellular biomarker for pharmacological inhibition of the histonedemethylase lysine-specific demethylase 1. Anal Biochem, 2013. 442(1):p. 104-6). CD86 expression is a marker of maturation of dendritic cells(DCs) which are involved in antitumor immune response. Notably, CD86functions as a co-stimulatory factor to activate T cell proliferation(Greaves, P. and J. G. Gribben, The role of B7 family molecules inhematologic malignancy. Blood, 2013. 121(5): p. 734-44; Chen, L. and D.B. Flies, Molecular mechanisms of T cell co-stimulation andco-inhibition. Nat Rev Immunol, 2013. 13(4): p. 227-42).

In addition to playing a role in cancer, LSD1 activity has also beenassociated with viral pathogenesis. Particularly, LSD1 activity appearsto be linked with viral replications and expressions of viral genes. Forexample, LSD1 functions as a co-activator to induce gene expression fromthe viral immediate early genes of various type of herpes virusincluding herpes simplex virus (HSV), varicella zoster virus (VZV), andβ-herpesvirus human cytomegalovirus (Liang, Y., et al., Targeting theJMJD2 histone demethylases to epigenetically control herpesvirusinfection and reactivation from latency. Sci Transl Med, 2013. 5(167):p. 167ra5; Liang, Y., et al., Inhibition of the histone demethylase LSD1blocks alpha-herpesvirus lytic replication and reactivation fromlatency. Nat Med, 2009. 15(11): p. 1312-7). In this setting, a LSD1inhibitor showed antiviral activity by blocking viral replication andaltering virus associated gene expression.

Recent studies have also shown that the inhibition of LSD1 by eithergenetic depletion or pharmacological intervention increased fetal globingene expression in erythroid cells (Shi, L., et al., Lysine-specificdemethylase 1 is a therapeutic target for fetal hemoglobin induction.Nat Med, 2013. 19(3): p. 291-4; Xu, J., et al., Corepressor-dependentsilencing of fetal hemoglobin expression by BCL11A. Proc Natl Acad SciUSA, 2013. 110(16): p. 6518-23). Inducing fetal globin gene would bepotentially therapeutically beneficial for the disease ofβ-globinopathies, including β-thalassemia and sickle cell disease wherethe production of normal β-globin, a component of adult hemoglobin, isimpaired (Sankaran, V. G. and S. H. Orkin, The switch from fetal toadult hemoglobin. Cold Spring Harb Perspect Med, 2013. 3(1): p. a011643;Bauer, D. E., S. C. Kamran, and S. H. Orkin, Reawakening fetalhemoglobin: prospects for new therapies for the beta-globin disorders.Blood, 2012. 120(15): p. 2945-53). Moreover, LSD1 inhibition maypotentiate other clinically used therapies, such as hydroxyurea orazacitidine. These agents may act, at least in part, by increasingγ-globin gene expression through different mechanisms.

In summary, LSD1 contributes to tumor development by altering epigeneticmarks on histones and non-histone proteins. Accumulating data havevalidated that either genetic depletion or pharmacological interventionof LSD1 normalizes altered gene expressions, thereby inducingdifferentiation programs into mature cell types, decreasing cellproliferation, and promoting apoptosis in cancer cells. Therefore, LSD1inhibitors alone or in combination with established therapeutic drugswould be effective to treat the diseases associated with LSD1 activity.

SUMMARY OF THE INVENTION

The present invention is directed to, inter alia, a compound of FormulaI:

or a pharmaceutically acceptable salt thereof, wherein constituentvariables are defined herein.

The present invention is further directed to a pharmaceuticalcomposition comprising a compound of Formula I and at least onepharmaceutically acceptable carrier.

The present invention is further directed to a method of inhibiting LSD1comprising contacting the LSD1 with a compound of Formula I.

The present invention is further directed to a method of treating anLSD1-mediated disease in a patient comprising administering to thepatient a therapeutically effective amount of a compound of Formula I.

DETAILED DESCRIPTION

The present invention provides, inter alia, LSD1-inhibiting compoundssuch as a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X is N or CR^(X);

Ring A is C₆₋₁₀ aryl or 5-10 membered heteroaryl comprising carbon and1, 2, 3, or 4 heteroatoms selected from N, O, and S, wherein said C₆₋₁₀aryl and 5-10 membered heteroaryl are each optionally substituted by 1,2, 3, or 4 substituents independently selected from R^(A);

Ring B is C₆₋₁₀ aryl; 5-10 membered heteroaryl comprising carbon and 1,2, 3 or 4 heteroatoms selected from N, O, and S; C₃₋₁₀ cycloalkyl; or4-10 membered heterocycloalkyl comprising carbon and 1, 2, 3, or 4heteroatoms selected from N, O, and S; wherein said C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl, and 4-10 memberedheterocycloalkyl are each optionally substituted by 1, 2, 3, or 4substituents independently selected from R^(B);

R¹ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, Cy¹,CN, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1),C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), or S(O)₂NR^(c1)R^(d1);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from Cy¹, halo, CN, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1),NR^(c1)(O)NR^(c1)R^(d1), C(′NR^(e1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1),N^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),and S(O)₂NR^(c1)R^(d1);

wherein when X is CR^(X), then R¹ is not CN;

R² is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₂₋₆ haloalkyl, Cy²,CN, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2)), C(═NR^(e2))R^(b2),C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), or S(O)₂NR^(c2)R^(d2);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from Cy², halo, CN, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2),NR^(c2)(O)NR^(c2)R^(d2), C(′NR^(e2))R^(b2), C(═NR^(e2))NR^(c2)R^(d2),N^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),and S(O)₂NR^(c2)R^(d2);

each R^(A) is independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a4), SR^(a4),C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4)), C(═NR^(e4))R^(b4),C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, C₁₋₆ haloalkyl, CN, NO₂, OR^(a4), SR^(a4),C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)(O)NR^(c4)R^(d4), C(′NR^(e4))R^(b4),C(′NR^(e4))NR^(c4)R^(d4), N^(c4)C(′NR^(e4))NR^(c4)R^(d4),NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4).

each R^(B) is independently selected from Cy³, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5)), C(═NR^(e5))R^(b5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5),S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, C₁₋₆ haloalkyl, CN, NO₂, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)(O)NR^(c5)R^(d5), C(═NR^(e5))R^(b5),C(═NR^(e5))NR^(c5)R^(d5), N^(c5)C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5),S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5);

R^(X) is independently selected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a7), SR^(a7), C(O)R^(b7),C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7), OC(O)NR^(c7)R^(d7),NR^(c7)R^(d7), NR^(c7)C(O)R^(b7), NR^(c7)C(O)OR^(a7),NR^(c7)C(O)NR^(c7)R^(d7)), C(═NR^(e7))R^(b7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7),NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7),and S(O)₂NR^(c7)R^(d7);

each Cy¹, Cy², Cy³, and Cy⁴ is independently selected from C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl, each of which is optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(Cy);

each R^(Cy) is independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₄ alkyl-, C₃₋₇ cycloalkyl-C₁₋₄ alkyl-, (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₄alkyl-, CN, NO₂, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6), NR^(c6)C(O)NR^(c6)R^(d6)),C(αNR^(e6))R^(b6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)S(O)R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6),and S(O)₂NR^(c6)R^(d6), wherein said C₁₋₄ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₄ alkyl-, C₃₋₇ cycloalkyl-C₁₋₄ alkyl-, (5-6membered heteroaryl)-C₁₋₄ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted by 1, 2,or 3 substituents independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, NO₂, OR^(a6), SR^(a6), C(O)R^(b6),C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6),NR^(c6)R^(d6), NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6),NR^(c6)C(O)NR^(c6)R^(d6)), C(═NR^(e6))R^(b6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(αNR^(e6))NR^(c6)R^(d6), NR^(c6)S(O)R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6),and S(O)₂NR^(c6)R^(d6);

each R^(a1) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and Cy⁴; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, or 3 substituentsindependently selected from Cy⁴, halo, CN, NO₂, OR^(a3), SR^(a3),C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3)), C(+NR^(e3))R^(b3),C(+NR^(e3))NR^(c3)R^(d3), NR^(c3)C(+NR^(e3))NR^(c3)R^(d3),NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3),S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3);

each R^(b1), R^(c1), and R^(d1) is independently selected from H, C₁₋₆alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted with 1, 2,3, 4, or 5 substituents independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a7), SR^(a7), C(O)R^(b7),C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7), OC(O)NR^(c7)R^(d7),NR^(c7)R^(d7), NR^(c7)C(O)R^(b7), NR^(c7)C(O)OR^(a7),NR^(c7)C(O)NR^(c7)R^(d7)), C(═NR^(e7))R^(b7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(c7))NR^(c7)R^(d7), NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7),NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7),and S(O)₂NR^(c7)R^(d7);

or any R^(c1) and R^(d1) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7)), C(═NR^(e7))R^(b7),C(═NR^(e7))NR^(c7)R^(d7), NR^(c7)C(═NR^(c7))NR^(c7)R^(d7),NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7),S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7), and S(O)₂NR^(c7)R^(d7),wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,C₆₋₁₀ aryl, and 5-6 membered heteroaryl are each optionally substitutedby 1, 2, or 3 substituents independently selected from halo, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a7), SR^(a7), C(O)R^(b7),C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7), OC(O)NR^(c7)R^(d7),NR^(c7)R^(d7), NR^(c7)C(O)R^(b7), NR^(c7)C(O)OR^(a7),NR^(c7)C(O)NR^(c7)R^(d7)), C(═NR^(e7))R^(b7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(c7))NR^(c7)R^(d7), NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7),NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7),and S(O)₂NR^(c7)R^(d7);

each R^(a2), R^(b2), R^(c2), and R^(d2) is independently selected fromH, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a7),SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7),OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7)), C(═NR^(e7))R^(b7),C(═NR^(e7))NR^(c7)R^(d7), NR^(c7)C(═NR^(c7))NR^(c7)R^(d7),NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7),S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7), and S(O)₂NR^(c7)R^(d7);

or any R^(c2) and R^(d2) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl, halo,CN, OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7)), C(═NR^(e7))R^(b7),C(═NR^(e7))NR^(c7)R^(d7), NR^(c7)C(═NR^(c7))NR^(c7)R^(d7),NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7),S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7), and S(O)₂NR^(c7)R^(d7),wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,phenyl, and 5-6 membered heteroaryl are each optionally substituted by1, 2, or 3 substituents independently selected from halo, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a7), SR^(a7), C(O)R^(b7),C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7), OC(O)NR^(c7)R^(d7),NR^(c7)R^(d7), NR^(c7)C(O)R^(b7), NR^(c7)C(O)OR^(a7),NR^(c7)C(O)NR^(c7)R^(d7)), C(═NR^(e7))R^(b7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(c7))NR^(c7)R^(d7), NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7),NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7),and S(O)₂NR^(c7)R^(d7);

each R^(a1), R^(b3), R^(c3), and R^(d3) is independently selected fromH, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a7),SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7),OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7)), C(═NR^(e7))R^(b7),C(═NR^(e7))NR^(c7)R^(d7), NR^(c7)C(═NR^(c7))NR^(c7)R^(d7),NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7),S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7), and S(O)₂NR^(c7)R^(d7);

or any R^(c3) and R^(d3) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl, halo,CN, OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7)), C(═NR^(e7))R^(b7),C(═NR^(e7))NR^(c7)R^(d7), NR^(c7)C(═NR^(c7))NR^(c7)R^(d7),NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7),S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7), and S(O)₂NR^(c7)R^(d7),wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,phenyl, and 5-6 membered heteroaryl are each optionally substituted by1, 2, or 3 substituents independently selected from halo, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a7), SR^(a7), C(O)R^(b7),C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7), OC(O)NR^(c7)R^(d7),NR^(c7)R^(d7), NR^(c7)C(O)R^(b7), NR^(c7)C(O)OR^(a7),NR^(c7)C(O)NR^(c7)R^(d7)), C(═NR^(e7))R^(b7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(c7))NR^(c7)R^(d7), NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7),NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7),and S(O)₂NR^(c7)R^(d7);

each R^(a4), R^(b4), R^(c4), and R^(d4) is independently selected fromH, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a7),SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7),OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7)), C(═NR^(e7))R^(b7),C(═NR^(e7))NR^(c7)R^(d7), NR^(c7)C(═NR^(c7))NR^(c7)R^(d7),NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7),S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7), and S(O)₂NR^(c7)R^(d7);

or any R^(c4) and R^(d4) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a7), SR^(a7),C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7),OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7)), C(═NR^(e7))R^(b7),C(═NR^(e7))NR^(c7)R^(d7), NR^(c7)C(═NR^(c7))NR^(c7)R^(d7),NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7),S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7), and S(O)₂NR^(c7)R^(d7);

each R^(a5), R^(b5), R^(c5), and R^(d5) is independently selected fromH, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a7),SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7),OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7)), C(═NR^(e7))R^(b7),C(═NR^(e7))NR^(c7)R^(d7), NR^(c7)C(═NR^(c7))NR^(c7)R^(d7),NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7),S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7), and S(O)₂NR^(c7)R^(d7);

or any R^(c5) and R^(d5) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7)), C(═NR^(e7))R^(b7),C(═NR^(e7))NR^(c7)R^(d7), NR^(c7)C(═NR^(c7))NR^(c7)R^(d7),NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7),S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7), and S(O)₂NR^(c7)R^(d7),wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,C₆₋₁₀ aryl, and 5-6 membered heteroaryl are each optionally substitutedby 1, 2, or 3 substituents independently selected from halo, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a7), SR^(a7), C(O)R^(b7),C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7), OC(O)NR^(c7)R^(d7),NR^(c7)R^(d7), NR^(c7)C(O)R^(b7), NR^(c7)C(O)OR^(a7),NR^(c7)C(O)NR^(c7)R^(d7)), C(═NR^(e7))R^(b7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(c7))NR^(c7)R^(d7), NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7),NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7),and S(O)₂NR^(c7)R^(d7);

each R^(a6), R^(b6), R^(c6), and R^(d6) is independently selected fromH, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a7),SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7),OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7)), C(═NR^(e7))R^(b7),C(═NR^(e7))NR^(c7)R^(d7), NR^(c7)C(═NR^(c7))NR^(c7)R^(d7),NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7),S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7), and S(O)₂NR^(c7)R^(d7);

or any R^(c6) and R^(d6) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a7), SR^(a7),C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7),OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7)), C(═NR^(e7))R^(b7),C(═NR^(e7))NR^(c7)R^(d7), NR^(c7)C(═NR^(c7))NR^(c7)R^(d7),NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7),S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7), and S(O)₂NR^(c7)R^(d7);

each R^(a7), R^(b7), R^(c7), and R^(d7) is independently selected fromH, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂-4 alkenyl, and C₂₋₄ alkynyl, whereinsaid C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl are each optionallysubstituted with 1, 2, or 3 substituents independently selected from OH,CN, amino, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;and

each R^(e1), R^(e2), R^(e3), R^(e4), R^(e5), R^(e6), and R⁷ selectedfrom H, C₁₋₄ alkyl, and CN.

In some embodiments:

X is N or CR^(X);

Ring A is phenyl or 5-10 membered heteroaryl comprising carbon and 1, 2,3, or 4 heteroatoms selected from N, O, and S, wherein said C₆₋₁₀ aryland 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3,or 4 substituents independently selected from R^(A);

Ring B is phenyl or 5-6 membered heteroaryl comprising carbon and 1, 2,3 or 4 heteroatoms selected from N, O, and S; wherein said phenyl and5-6 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4substituents independently selected from R^(B);

R¹ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, Cy¹,CN, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1),C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), or S(O)₂NR^(c1)R^(d1);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from Cy¹, halo, CN, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1),NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),and S(O)₂NR^(c1)R^(d1);

wherein when X is CR^(X), then R¹ is not CN;

R² is H, halo, C₁₋₆ alkyl, CN, OR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), S(O)₂R^(b2), or S(O)₂NR^(c2)R^(d2);wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, or 3substituents independently selected from halo, CN, OR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), S(O)₂R^(b2), orS(O)₂NR^(c2)R^(d2);

each R^(A) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, CN, OR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), NR^(c4)R^(d4),NR^(c4)C(O)R^(b4), S(O)₂R^(b4), or S(O)₂NR^(c4)R^(d4); wherein said C₁₋₆alkyl is optionally substituted by 1, 2, or 3, substituentsindependently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN,OR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), NR^(c4)R^(d4),NR^(c4)C(O)R^(b4), S(O)₂R^(b4), or S(O)₂NR^(c4)R^(d4);

each R^(B) is independently selected from Cy³, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5); C(O)OR^(a5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5), wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are each optionally substituted by 1, 2, or 3substituents independently selected from Cy³, halo, C₁₋₆ haloalkyl, CN,NO₂, OR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), S(O)₂R^(b5), or S(O)₂NR^(c5)R^(d5);

R^(X) is independently selected from H, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, CN, OR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), NR^(c7)R^(d7),NR^(c7)C(O)R^(b7), S(O)₂R^(b7), or S(O)₂NR^(c7)R^(d7);

each Cy¹, Cy³, and Cy⁴ is independently selected from C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl, each of which is optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(Cy);

each R^(Cy) is independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₄ alkyl-, C₃₋₇ cycloalkyl-C₁₋₄ alkyl-, (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₄alkyl-, CN, NO₂, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6), NR^(c6)C(O)NR^(c6)R^(d6)),C(αNR^(e6))R^(b6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)S(O)R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6),and S(O)₂NR^(c6)R^(d6), wherein said C₁₋₄ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₄ alkyl-, C₃₋₇ cycloalkyl-C₁₋₄ alkyl-, (5-6membered heteroaryl)-C₁₋₄ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted by 1, 2,or 3 substituents independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, NO₂, OR^(a6), SR^(a6), C(O)R^(b6),C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6),NR^(c6)R^(d6), NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6),NR^(c6)C(O)NR^(c6)R^(d6)), C(αNR^(e6))R^(b6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)S(O)R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6),and S(O)₂NR^(c6)R^(d6);

each R^(a1) is independently selected from H, C₁₋₆ alkyl, and Cy⁴;wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, or 3substituents independently selected from Cy⁴, halo, CN, OR^(a3),C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3);

each R^(b1), R^(c1), and R^(d1) is independently selected from H, C₁₋₆alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted with 1, 2,3, 4, or 5 substituents independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a7), SR^(a7), C(O)R^(b7),C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7), OC(O)NR^(c7)R^(d7),NR^(c7)R^(d7), NR^(c7)C(O)R^(b7), NR^(c7)C(O)NR^(c7)R^(d7),NR^(c7)C(O)OR^(a7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7),

or any R^(c1) and R^(a1) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areeach optionally substituted by 1, 2, or 3 substituents independentlyselected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN,OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

each R^(a2), R^(b2), R^(c2), and R^(d2) is independently selected fromH, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a7),SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7),OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)R^(b7), NR^(c7)C(O)R^(d7),NR^(c7)C(O)OR^(a7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

or any R^(c2) and R^(d2) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl, halo,CN, OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(b7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂R^(c7)R^(b7), andS(O)₂NR^(c7)R^(d7), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are eachoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a7),SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7),OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7)), C(═NR^(e7))R^(b7),C(═NR^(e7))NR^(c7)R^(d7), NR^(c7)C(═NR^(c7))NR^(c7)R^(d7),NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7),S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7), and S(O)₂NR^(c7)R^(d7);

each R^(a3), R^(b3), R^(c3), and R^(d3) is independently selected fromH, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₄ alkyl-, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₄ alkyl- are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a7),SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7),OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))R^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

or any R^(c3) and R^(d3) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl, halo,CN, OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))R^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are eachoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a7),SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7),OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))R^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

each R^(a4), R^(b4), R^(c4), and R^(d4) independently selected from H,C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a7),SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7),OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))R^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

or any R^(c4) and R^(d4) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a7), SR^(a7),C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7),OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))R^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

each R^(a5), R^(b5), R^(c5), and R^(d5) is independently selected fromH, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a7),SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7),OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))R^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

or any R^(c5) and R^(d5) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))R^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areeach optionally substituted by 1, 2, or 3 substituents independentlyselected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN,OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))R^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

each R^(a6), R^(b6), R^(c6) and R^(d6) is independently selected from H,C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a7),SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7),OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))R^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

or any R^(c6) and R^(d6) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a7), SR^(a7),C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7),OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))R^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

each R^(a7), R^(b7), R^(c7), and R^(d7) is independently selected fromH, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂-4 alkenyl, and C₂₋₄ alkynyl, whereinsaid C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl are each optionallysubstituted with 1, 2, or 3 substituents independently selected from OH,CN, amino, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;and

each R^(e1), R^(e6), and R^(e7) independently selected from H, C₁₋₄alkyl, and CN.

In some embodiments:

X is N or CR^(X);

Ring A is phenyl optionally substituted by 1 or 2 substituentsindependently selected from R^(A);

Ring B is phenyl optionally substituted by 1 or 2 substituentsindependently selected from R^(B);

R¹ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, Cy¹,OR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), NR^(c1)C(O)R^(b1),S(O)R^(b1), S(O)₂NR^(c1)R^(d1) wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl are each optionally substituted with 1, 2, or 3substituents independently selected from Cy¹, halo, CN, OR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), NR^(c1)R^(d1),NR^(c1)(C(O)R^(b1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);

R² is H;

each R^(A) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, CN, and OR¹, wherein said C₁₋₆ alkyl is optionallysubstituted by 1, 2, or 3, substituents independently selected from CNand OR^(a4);

each R^(B) is independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, and OR^(a5);

R^(X) is H;

each Cy¹ and Cy⁴ is independently selected from phenyl, C₃₋₇ cycloalkyl,5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, each ofwhich is optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(Cy);

each R is independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ cyanoalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, OR^(a6), SR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)OR^(a6), NR^(c6)C(O)NR^(c6)R^(d6)), C(αNR^(e6))R^(b6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)S(O)R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6),S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6),wherein said C₁₋₄ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, are each optionallysubstituted by 1, 2, or 3 substituents independently selected from C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, NO₂, OR^(a6), SR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)OR^(a6), NR^(c6)C(O)NR^(c6)R^(d6)), C(αNR^(e6))R^(b6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)S(O)R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6),S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6);

each R^(a1) is independently selected from H, C₁₋₆ alkyl, and 4-7membered heterocycloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, or 3 substituents independently selected fromCy⁴, halo, CN, OR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3),and wherein said 4-7 membered heterocycloalkyl is optionally substitutedwith 1, 2, or 3 substituents independently selected from halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂, OR^(a6), C(O)R^(b6),C(O)NR^(c6)R^(d6), C(O)OR^(a6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6);

each R^(b1), R^(c1), and R^(d1) is independently selected from H, C₁₋₆alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₄ alkyl-, C₃₋₇ cycloalkyl-C₁₋₄ alkyl-, (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl,C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₄ alkyl-, C₃₋₇ cycloalkyl-C₁₋₄ alkyl-, (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-are each optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl,halo, CN, OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), S(O)R^(b7),S(O)NR^(c7)R^(d7), S(O)₂R^(b7), a NR^(c7)(S(O)₂R^(b7),NR^(c7)S(O)₂NR^(c7)R^(d7), and S(O)₂NR^(c7)R^(d7);

or any R^(c1) and R^(d1) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), S(O)R^(b7),S(O)NR^(c7)R^(d7), S(O)₂R^(b7), a NR^(c7)(S(O)₂R^(b7),NR^(c7)S(O)₂NR^(c7)R^(d7), and S(O)₂NR^(c7)R^(d7), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a7), SR^(a7), C(O)R^(b7),C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7), OC(O)NR^(c7)R^(d7),NR^(c7)R^(d7), NR^(c7)C(O)R^(b7), NR^(c7)C(O)NR^(c7)R^(d7),NR^(c7)C(O)OR^(a7), S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7), aNR^(c7)(S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), and S(O)₂NR^(c7)R^(d7);

each R^(a3), R^(b3), R^(c3), and R^(d3) is independently selected from Hand C₁₋₆ alkyl;

each R^(a4) is independently selected from H and C₁₋₆ alkyl;

each R^(a5) is independently selected from H and C₁₋₆ alkyl;

each R^(a6), R^(b6), R^(c6), and R^(d6) is independently selected from Hand C₁₋₆ alkyl; and

each R^(a7), R^(b7), R^(c7), and R^(d7) is independently selected from Hand C₁₋₄ alkyl.

In some embodiments, X is N.

In some embodiments, X is CR^(X).

In some embodiments, Ring A is phenyl or 5-10 membered heteroarylcomprising carbon and 1, 2, 3, or 4 heteroatoms selected from N, O, andS, wherein said C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted by 1, 2, 3, or 4 substituents independentlyselected from R^(A).

In some embodiments, Ring A is phenyl optionally substituted by 1 or 2substituents independently selected from R^(A).

In some embodiments, Ring A is phenyl substituted by one R^(A).

In some embodiments, Ring A is phenyl substituted by CN.

In some embodiments, Ring B is phenyl or 5-6 membered heteroarylcomprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, andS; wherein said phenyl and 5-6 membered heteroaryl are each optionallysubstituted by 1, 2, 3, or 4 substituents independently selected fromR^(B).

In some embodiments, Ring B is phenyl optionally substituted by 1 or 2substituents independently selected from R^(B).

In some embodiments, Ring B is phenyl substituted by one R^(B).

In some embodiments, Ring B is phenyl substituted by methyl.

In some embodiments, R¹ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, Cy¹, OR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), NR^(c1)R^(d1), NR^(c1)(C(O)R^(b1), S(O)₂R^(b1), andS(O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, or 3 substituentsindependently selected from Cy¹, halo, CN, OR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), NR^(c1)R^(d1), NR^(c1)(C(O)R^(b1),S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1).

In some embodiments, R¹ is C₁₋₆ alkyl, Cy¹, or OR¹, wherein said C₁₋₆alkyl is substituted with one Cy¹.

In some embodiments, R¹ is pyrrolidin-3-ylmethoxy,2-pyrrolidin-3-ylethyl, (1-methylpyrrolidin-3-yl)ethyl,3-[(methylamino)methyl]phenyl, 3-aminopyrrolidin-1-yl)methyl]phenyl,piperazin-1-ylmethyl, 4-methylpiperazin-1-yl)methyl,3-(dimethylamino)pyrrolidin-1-yl, 3-(methylamino)pyrrolidin-1-yl, or(1-methylpyrrolidin-3-yl)methoxy.

In some embodiments, R² is H.

In some embodiments, each R^(A) is independently selected from halo,C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, OR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4),C(O)OR^(a4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), S(O)₂R^(b4), andS(O)₂NR^(c4)R^(d4), wherein said C₁₋₆ alkyl is optionally substituted by1, 2, or 3, substituents independently selected from halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, CN, OR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4).

In some embodiments, each R^(A) is independently selected from halo,C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, and OR^(a4), wherein said C₁₋₆ alkyl isoptionally substituted by 1, 2, or 3, substituents independentlyselected from CN and OR^(a4).

In some embodiments, R^(A) is CN.

In some embodiments, each R^(B) is independently selected from Cy³,halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂,OR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5), wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted by 1, 2, or 3 substituents independently selected from Cy³,halo, C₁₋₆ haloalkyl, CN, NO₂, OR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),C(O)OR^(a5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), S(O)₂R^(b5), andS(O)₂NR^(c5)R^(d5).

In some embodiments, each R^(B) is independently selected from halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, and OR^(a5).

In some embodiments, R^(B) is C₁₋₆ alkyl.

In some embodiments, R^(B) is methyl.

In some embodiments, R^(X) is H.

In some embodiments, each Cy¹ is independently selected from phenyl,C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl, each of which is optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(Cy).

In some embodiments, each Cy¹ is phenyl or 4-7 memberedheterocycloalkyl, each optionally substituted with 1 or 2 substituentsindependently selected from R^(Cy).

In some embodiments, each Cy¹ is phenyl, pyrrolidinyl, or piperazinyl,each optionally substituted with 1 or 2 substituents independentlyselected from R^(Cy).

In some embodiments, each Cy¹ is phenyl, pyrrolidinyl, or piperazinyl,each optionally substituted with 1 or 2 substituents independentlyselected from C₁₋₄ alkyl and NR^(c6)R^(d6), wherein said C₁₋₄ alkyl isoptionally substituted with NR^(c6)R^(d6).

In some embodiments, each R^(Cy) is C₁₋₄ alkyl and NR^(c6)R^(d6),wherein said C₁₋₄ alkyl is optionally substituted with NR^(c6)R^(d6).

In some embodiments, each R^(a1) is independently selected from H, C₁₋₆alkyl, and Cy⁴; wherein said C₁₋₆ alkyl is optionally substituted with1, 2, or 3 substituents independently selected from Cy⁴, halo, CN,OR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3).

In some embodiments, each R^(a1) is independently selected from H, C₁₋₆alkyl, and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from Cy⁴, halo, CN, OR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), S(O)₂R^(b3), andS(O)₂NR^(c3)R^(d3), and wherein said 4-7 membered heterocycloalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN,NO₂, OR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6).

In some embodiments, each R^(a1) is C₁₋₄ alkyl substituted by 4-7membered heterocycloalkyl, wherein said 4-7 membered heterocycloalkyl isoptionally substituted with 1 or 2 substituents independently selectedfrom halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂,OR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6).

In some embodiments, each R^(a1) is pyrrolidinylmethyl optionallysubstituted with one C₁₋₄ alkyl.

In some embodiments, the compounds of the invention have Formula IIa:

In some embodiments, the compounds of the invention have Formula IIb:

In some embodiments, the compounds of the invention have Formula IIa:

In some embodiments, the compounds of the invention have Formula IIb:

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, can also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention which are, for brevity, described in thecontext of a single embodiment, can also be provided separately or inany suitable subcombination.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted. As used herein, the term “substituted” means that ahydrogen atom is removed and replaced by a monovalent substituent, ortwo hydrogen atoms are replaced with a divalent substituent like aterminal oxo group. It is to be understood that substitution at a givenatom is limited by valency.

Throughout the definitions, the term “C_(i-j)” indicates a range whichincludes the endpoints, wherein i and j are integers and indicate thenumber of carbons. Examples include C₁₋₄, C₁₋₆, and the like.

The term “z-membered” (where z is an integer) typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is z. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

As used herein, the term “C_(i-j)alkyl,” employed alone or incombination with other terms, refers to a saturated hydrocarbon groupthat may be straight-chain or branched, having i to j carbons. In someembodiments, the alkyl group contains from 1 to 6 carbon atoms or from 1to 4 carbon atoms, or from 1 to 3 carbon atoms. Examples of alkylmoieties include, but are not limited to, chemical groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, and t-butyl.

As used herein, the term “C_(i-j) alkoxy,” employed alone or incombination with other terms, refers to a group of formula —O-alkyl,wherein the alkyl group has i to j carbons. Example alkoxy groupsinclude methoxy, ethoxy, and propoxy (e.g., n-propoxy and isopropoxy).In some embodiments, the alkyl group has 1 to 3 carbon atoms.

As used herein, “C_(i-j) alkenyl,” employed alone or in combination withother terms, refers to an unsaturated hydrocarbon group having one ormore double carbon-carbon bonds and having i to j carbons. In someembodiments, the alkenyl moiety contains 2 to 6 or 2 to 4 carbon atoms.Example alkenyl groups include, but are not limited to, ethenyl,n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

As used herein, “C_(i-j) alkynyl,” employed alone or in combination withother terms, refers to an unsaturated hydrocarbon group having one ormore triple carbon-carbon bonds and having i to j carbons. Examplealkynyl groups include, but are not limited to, ethynyl, propyn-1-yl,propyn-2-yl, and the like. In some embodiments, the alkynyl moietycontains 2 to 6 or 2 to 4 carbon atoms.

As used herein, the term “C_(i-j) alkylamino,” employed alone or incombination with other terms, refers to a group of formula —NH(alkyl),wherein the alkyl group has i to j carbon atoms. In some embodiments,the alkyl group has 1 to 6 or 1 to 4 carbon atoms. In some embodiments,the alkylamino group is NH(C₁₋₄ alkyl) such as, for example,methylamino, ethylamino or propylamino.

As used herein, the term “di-C_(i-j)alkylamino,” employed alone or incombination with other terms, refers to a group of formula —N(alkyl)₂,wherein each of the two alkyl groups has, independently, i to j carbonatoms. In some embodiments, each alkyl group independently has 1 to 6 or1 to 4 carbon atoms. In some embodiments, the dialkylamino group is—N(C₁₋₄ alkyl)₂ such as, for example, dimethylamino or diethylamino.

As used herein, the term “C_(i-j) alkylthio,” employed alone or incombination with other terms, refers to a group of formula —S-alkyl,wherein the alkyl group has i to j carbon atoms. In some embodiments,the alkyl group has 1 to 6 or 1 to 4 carbon atoms. In some embodiments,the alkylthio group is C₁₋₄ alkylthio such as, for example, methylthioor ethylthio.

As used herein, the term “amino,” employed alone or in combination withother terms, refers to a group of formula —NH₂.

As used herein, the term “aryl,” employed alone or in combination withother terms, refers to a monocyclic or polycyclic (e.g., having 2, 3 or4 fused rings) aromatic hydrocarbon, such as, but not limited to,phenyl, 1-naphthyl, 2-naphthyl, anthracenyl, phenanthrenyl, and thelike. In some embodiments, aryl is C₆₋₁₀ aryl. In some embodiments, thearyl group is a naphthalene ring or phenyl ring. In some embodiments,the aryl group is phenyl.

As used herein, the term “aryl-C_(i-j) alkyl,” employed alone or incombination with other terms, refers to an alkyl group substituted by anaryl group. An example of a aryl-C_(i-j) alkyl group is benzyl.

As used herein, the term “carbonyl”, employed alone or in combinationwith other terms, refers to a —C(O)— group.

As used herein, the term “C_(i-j) cycloalkyl,” employed alone or incombination with other terms, refers to a non-aromatic cyclichydrocarbon moiety having i to j ring-forming carbon atoms, which mayoptionally contain one or more alkenylene groups as part of the ringstructure. Cycloalkyl groups can include mono- or polycyclic (e.g.,having 2, 3 or 4 fused rings) ring systems. Also included in thedefinition of cycloalkyl are moieties that have one or more aromaticrings fused (i.e., having a bond in common with) to the cycloalkyl ring,for example, benzo derivatives of cyclopentane, cyclopentene,cyclohexane, and the like. One or more ring-forming carbon atoms of acycloalkyl group can be oxidized to form carbonyl linkages. In someembodiments, cycloalkyl is C₃₋₁₀ cycloalkyl, C₃₋₇ cycloalkyl, or C₅₋₆cycloalkyl. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl,cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, andthe like. Further exemplary cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.

As used herein, the term “C_(i-j) cycloalkyl-C_(i-j) alkyl,” employedalone or in combination with other terms, refers to an alkyl groupsubstituted by a cycloalkyl group. An example of a C_(i-j)cycloalkyl-C_(i-j) alkyl group is cyclopropylmethyl.

As used herein, “C_(i-j) haloalkoxy,” employed alone or in combinationwith other terms, refers to a group of formula —O-haloalkyl having i toj carbon atoms. An example haloalkoxy group is OCF₃. An additionalexample haloalkoxy group is OCHF₂. In some embodiments, the haloalkoxygroup is fluorinated only. In some embodiments, the alkyl group has 1 to6 or 1 to 4 carbon atoms. In some embodiments, the haloalkoxy group isC₁₋₄ haloalkoxy.

As used herein, the term “halo,” employed alone or in combination withother terms, refers to a halogen atom selected from F, Cl, I or Br. Insome embodiments, “halo” refers to a halogen atom selected from F, Cl,or Br. In some embodiments, the halo substituent is F.

As used herein, the term “C_(i-j) haloalkyl,” employed alone or incombination with other terms, refers to an alkyl group having from onehalogen atom to 2s+1 halogen atoms which may be the same or different,where “s” is the number of carbon atoms in the alkyl group, wherein thealkyl group has i to j carbon atoms. In some embodiments, the haloalkylgroup is fluorinated only. In some embodiments, the haloalkyl group isfluoromethyl, difluoromethyl, or trifluoromethyl. In some embodiments,the haloalkyl group is trifluoromethyl. In some embodiments, the alkylgroup has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “heteroaryl,” employed alone or in combinationwith other terms, refers to a monocyclic or polycyclic (e.g., having 2,3 or 4 fused rings) aromatic heterocylic moiety, having one or moreheteroatom ring members selected from nitrogen, sulfur and oxygen. Insome embodiments, the heteroaryl group has 1, 2, 3, or 4 heteroatom ringmembers. In some embodiments, the heteroaryl group has 1, 2, or 3heteroatom ring members. In some embodiments, the heteroaryl group has 1or 2 heteroatom ring members. In some embodiments, the heteroaryl grouphas 1 heteroatom ring member. In some embodiments, the heteroaryl groupis 5- to 10-membered or 5- to 6-membered. In some embodiments, theheteroaryl group is 5-membered. In some embodiments, the heteroarylgroup is 6-membered. When the heteroaryl group contains more than oneheteroatom ring member, the heteroatoms may be the same or different.The nitrogen atoms in the ring(s) of the heteroaryl group can beoxidized to form N-oxides. Example heteroaryl groups include, but arenot limited to, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole,pyrazole, azolyl, oxazole, isoxazole, thiazole, isothiazole, imidazole,furan, thiophene, triazole, tetrazole, thiadiazole, quinoline,isoquinoline, indole, benzothiophene, benzofuran, benzisoxazole,imidazo[1,2-b]thiazole, purine, triazine, and the like.

A 5-membered heteroaryl is a heteroaryl group having five ring-formingatoms comprising wherein one or more of the ring-forming atoms areindependently selected from N, O, and S. In some embodiments, the5-membered heteroaryl group has 1, 2, or 3 heteroatom ring members. Insome embodiments, the 5-membered heteroaryl group has 1 or 2 heteroatomring members. In some embodiments, the 5-membered heteroaryl group has 1heteroatom ring member. Example ring-forming members include CH, N, NH,O, and S. Example five-membered ring heteroaryls are thienyl, furyl,pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl,isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl,1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl,1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and1,3,4-oxadiazolyl.

A 6-membered heteroaryl is a heteroaryl group having six ring-formingatoms wherein one or more of the ring-forming atoms is N. In someembodiments, the 6-membered heteroaryl group has 1, 2, or 3 heteroatomring members. In some embodiments, the 6-membered heteroaryl group has 1or 2 heteroatom ring members. In some embodiments, the 6-memberedheteroaryl group has 1 heteroatom ring member. Example ring-formingmembers include CH and N. Example six-membered ring heteroaryls arepyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

As used herein, the term “heteroaryl-C_(i-j) alkyl,” employed alone orin combination with other terms, refers to an alkyl group substituted bya heteroaryl group. An example of a heteroaryl-C_(i-j) alkyl group ispyridylmethyl.

As used herein, the term “heterocycloalkyl,” employed alone or incombination with other terms, refers to non-aromatic heterocyclic ringsystem, which may optionally contain one or more unsaturations as partof the ring structure, and which has at least one heteroatom ring memberindependently selected from nitrogen, sulfur and oxygen. In someembodiments, the heterocycloalkyl group has 1, 2, 3, or 4 heteroatomring members. In some embodiments, the heterocycloalkyl group has 1, 2,or 3 heteroatom ring members. In some embodiments, the heterocycloalkylgroup has 1 or 2 heteroatom ring members. In some embodiments, theheterocycloalkyl group has 1 heteroatom ring member. When theheterocycloalkyl group contains more than one heteroatom in the ring,the heteroatoms may be the same or different. Example ring-formingmembers include CH, CH₂, C(O), N, NH, O, S, S(O), and S(O)₂.

Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2,3 or 4 fused rings) ring systems, including spiro systems. Also includedin the definition of heterocycloalkyl are moieties that have one or morearomatic rings fused (i.e., having a bond in common with) to thenon-aromatic ring, for example, 1,2,3,4-tetrahydro-quinoline,dihydrobenzofuran and the like. The carbon atoms or heteroatoms in thering(s) of the heterocycloalkyl group can be oxidized to form acarbonyl, sulfinyl, or sulfonyl group (or other oxidized linkage) or anitrogen atom can be quaternized. In some embodiments, theheterocycloalkyl is 5- to 10-membered, 4- to 10-membered, 4- to7-membered, 5-membered, or 6-membered. Examples of heterocycloalkylgroups include 1,2,3,4-tetrahydro-quinoline, dihydrobenzofuran,azetidine, azepane, pyrrolidine, piperidine, piperazine, morpholine,thiomorpholine, and pyran.

As used herein, the term “heterocycloalkyl-C_(i-j) alkyl,” employedalone or in combination with other terms, refers to an alkyl groupsubstituted by a heterocycloalkyl group. An example of aheterocycloalkyl-C_(i-j) alkyl group is pyrrolidinylmethyl.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereoisomers, are intended unless otherwise indicated. Compounds ofthe present invention that contain asymmetrically substituted carbonatoms can be isolated in optically active or racemic forms. Methods onhow to prepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

When the compounds of the invention contain a chiral center, thecompounds can be any of the possible stereoisomers. In compounds with asingle chiral center, the stereochemistry of the chiral center can be(R) or (S). In compounds with two chiral centers, the stereochemistry ofthe chiral centers can each be independently (R) or (S) so theconfiguration of the chiral centers can be (R) and (R), (R) and (S); (S)and (R), or (S) and (S). In compounds with three chiral centers, thestereochemistry each of the three chiral centers can each beindependently (R) or (S) so the configuration of the chiral centers canbe (R), (R) and (R); (R), (R) and (S); (R), (S) and (R); (R), (S) and(S); (S), (R) and (R); (S), (R) and (S); (S), (S) and (R); or (S), (S)and (S).

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such asβ-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofα-methylbenzylamine (e.g., S and R forms, or diastereoisomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-iminepairs, and annular forms where a proton can occupy two or more positionsof a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H-and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole.Tautomeric forms can be in equilibrium or sterically locked into oneform by appropriate substitution.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.

The term “compound” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,hydrates and solvates) or can be isolated.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in a compound of theinvention. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds of the invention, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The expressions, “ambient temperature” and “room temperature,” as usedherein, are understood in the art, and refer generally to a temperature,e.g., a reaction temperature, that is about the temperature of the roomin which the reaction is carried out, for example, a temperature fromabout 20° C. to about 30° C.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the conventionalnon-toxic salts of the parent compound formed, for example, fromnon-toxic inorganic or organic acids. The pharmaceutically acceptablesalts of the present invention can be synthesized from the parentcompound which contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting thefree acid or base forms of these compounds with a stoichiometric amountof the appropriate base or acid in water or in an organic solvent, or ina mixture of the two; generally, non-aqueous media like ether, ethylacetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) oracetonitrile (MeCN) are preferred. Lists of suitable salts are found inRemington's Pharmaceutical Sciences, 17^(th) Ed., (Mack PublishingCompany, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977,66(1), 1-19, and in Stahl et al., Handbook of Pharmaceutical Salts:Properties, Selection, and Use, (Wiley, 2002).

The following abbreviations may be used herein: AcOH (acetic acid); Ac₂O(acetic anhydride); aq. (aqueous); atm. (atmosphere(s)); Boc(t-butoxycarbonyl); BOP((benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate); br (broad); Cbz (carboxybenzyl); calc.(calculated); d (doublet); dd (doublet of doublets); DBU(1,8-diazabicyclo[5.4.0]undec-7-ene); DCM (dichloromethane); DIAD(N,N′-diisopropyl azidodicarboxylate); DIEA (N,N-diisopropylethylamine);DIPEA (N,N-diisopropylethylamine); DMF (N,N-dimethylformamide); Et(ethyl); EtOAc (ethyl acetate); g (gram(s)); h (hour(s)); HATU(N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate); HCl (hydrochloric acid); HPLC (high performanceliquid chromatography); Hz (hertz); IPA (isopropyl alcohol); J (couplingconstant); LCMS (liquid chromatography mass spectrometry); m(multiplet); M (molar); mCPBA (3-chloroperoxybenzoic acid); MS (Massspectrometry); Me (methyl); MeCN (acetonitrile); MeOH (methanol); mg(milligram(s)); min. (minutes(s)); mL (milliliter(s)); mmol(millimole(s)); N (normal); nM (nanomolar); NMP (N-methylpyrrolidinone);NMR (nuclear magnetic resonance spectroscopy); OTf(trifluoromethanesulfonate); Ph (phenyl); pM (picomolar); RP-HPLC(reverse phase high performance liquid chromatography); s (singlet); t(triplet or tertiary); TBS (tert-butyldimethylsilyl); tert (tertiary);tt (triplet of triplets); TFA (trifluoroacetic acid); THF(tetrahydrofuran); μg (microgram(s)); μL (microliter(s)); μM(micromolar); wt % (weight percent).

Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in P. G. M. Wuts and T. W.Greene, Protective Groups in Organic Synthesis, 4^(th) Ed., Wiley &Sons, Inc., New York (2006), which is incorporated herein by referencein its entirety.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry, or by chromatographic methods such as high performanceliquid chromatography (HPLC), liquid chromatography-mass spectroscopy(LCMS), or thin layer chromatography (TLC). Compounds can be purified bythose skilled in the art by a variety of methods, including highperformance liquid chromatography (HPLC) (“Preparative LC-MSPurification: Improved Compound Specific Method Optimization” Karl F.Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004,6(6), 874-883, which is incorporated herein by reference in itsentirety) and normal phase silica chromatography.

Compounds of formula 9 can be synthesized as shown in Scheme 1. Compound1 can undergo Suzuki reaction with an appropriate boronic acid or esterof formula 2 in the presence of a palladium catalyst and a suitable basesuch as K₂CO₃ to provide compound of formula 3. Installation of ring Bto give compound of formula 5 can be achieved by coupling of compound 3with compound of formula 4 under standard Suzuki coupling conditions (Mis a boronic acid or ester, with palladium catalysis), or standardNegishi coupling conditions (M is Zn-halo, in the presence of apalladium catalyst), or standard Buchwald amination conditions (M is Hattached to a ring-forming N atom in ring B, in the presence of apalladium catalyst and a suitable base). Halogenation of compound 5using N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide canprovide a compound of formula 6 (Hal is Cl, Br or I). Compound 6 can beconverted to a formamidoxime derivative of formula 7 by reacting withN,N-dimethylformamide dimethyl acetal, followed by treatment withhydroxylamine. The formamidoxime derivative 7 can undergo cyclizationupon treating with trifluoroacetic anhydride (TFAA) to afford a triazolecompound of formula 8. Finally, the aryl halide 8 can react with R^(t)-Mto give a compound of formula 9 under standard cross couplingconditions, such as Suzuki coupling conditions (M is a boronic acid orester, with palladium catalysis), Sonogashira coupling conditions (M isa terminal alkynyl, with palladium catalysis), Negishi couplingconditions (M is ZnCl, ZnBr or ZnI, with palladium catalysis), Buchwaldamination conditions (R¹-M is an amine (M is H), with palladiumcatalysis) or Ullmann coupling conditions (R′-M is an alcohol (M is H),with palladium or copper catalysis).

Compounds of formula 11, wherein R² is a non-hydrogen substituent, canbe synthesized as shown in Scheme 2. Compound 6, which can be preparedas described in Scheme 1, can react with a nitrile R²—CN to deliver atriazole compound of formula 10 via a copper-catalyzed tandemaddition-oxidative cyclization. This tandem reaction is described inNagasawa et. al. in J. Am. Chem. Soc. 2009, 131, 42, 15080. Finally, thearyl halide 10 can react with R¹-M under standard cross couplingconditions as described in Scheme 1 (e.g., Suzuki coupling, Negishicoupling, Sonogashira coupling, Buchwald amination or Ullmann coupling)to give compounds of formula 11.

Alternatively, compounds of formula 11 can be prepared as shown inScheme 3. Aryl halide 6 can react with R¹-M under standard crosscoupling conditions as described in Scheme 1 (e.g., Suzuki coupling,Negishi coupling, Sonogashira coupling, Buchwald amination or Ullmanncoupling) to give compounds of formula 12. Condensation ofamino-pyridine derivative 12 with ethoxycarbonyl isothiocyanate,followed by treatment with hydroxylamine can give the aminotriazole offormula 13. Transformation of the amino group in compound 13 to bromidecan be achieved under standard Sandmeyer reaction conditions (e.g.,NaNO₂, HBr then CuBr) to give compounds of formula 14. Functionalizationof aryl bromide 14 with an R² substituent to give compound 11 can beperformed under standard cross coupling reaction conditions (e.g.,Suzuki coupling, Negishi coupling, Sonogashira coupling, Buchwaldamination or Ullmann coupling) as described in the previous Schemes.

Methods of Use

Compounds of the invention are LSD1 inhibitors and, thus, are useful intreating diseases and disorders associated with activity of LSD1. Forthe uses described herein, any of the compounds of the invention,including any of the embodiments thereof, may be used.

In some embodiments, the compounds of the invention are selective forLSD1 over LSD2, meaning that the compounds bind to or inhibit LSD1 withgreater affinity or potency, compared to LSD2. In general, selectivitycan be at least about 5-fold, at least about 10-fold, at least about20-fold, at least about 50-fold, at least about 100-fold, at least about200-fold, at least about 500-fold or at least about 1000-fold.

As inhibitors of LSD1, the compounds of the invention are useful intreating LSD1-mediated diseases and disorders. The term “LSD1-mediateddisease” or “LSD1-mediated disorder” refers to any disease or conditionin which LSD1 plays a role, or where the disease or condition isassociated with expression or activity of LSD1. The compounds of theinvention can therefore be used to treat or lessen the severity ofdiseases and conditions where LSD1 is known to play a role.

Diseases and conditions treatable using the compounds of the inventioninclude generally cancers, inflammation, autoimmune diseases, viralinduced pathogenesis, beta-globinopathies, and other diseases linked toLSD1 activity.

Cancers treatable using compounds according to the present inventioninclude, for example, hematological cancers, sarcomas, lung cancers,gastrointestinal cancers, genitourinary tract cancers, liver cancers,bone cancers, nervous system cancers, gynecological cancers, and skincancers.

Example hematological cancers include, for example, lymphomas andleukemias such as acute lymphoblastic leukemia (ALL), acute myelogenousleukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocyticleukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-celllymphoma (DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (includingrelapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma,myeloproliferative diseases (e.g., primary myelofibrosis (PMF),polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplasiasyndrome (MDS), and multiple myeloma.

Example sarcomas include, for example, chondrosarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma,myxoma, rhabdomyoma, fibroma, lipoma, harmatoma, and teratoma.

Example lung cancers include, for example, non-small cell lung cancer(NSCLC), bronchogenic carcinoma (squamous cell, undifferentiated smallcell, undifferentiated large cell, adenocarcinoma), alveolar(bronchiolar) carcinoma, bronchial adenoma, chondromatous hamartoma, andmesothelioma.

Example gastrointestinal cancers include, for example, cancers of theesophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma,lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas(ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoidtumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoidtumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma,fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma), and colorectal cancer.

Example genitourinary tract cancers include, for example, cancers of thekidney (adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder andurethra (squamous cell carcinoma, transitional cell carcinoma,adenocarcinoma), prostate (adenocarcinoma, sarcoma), and testis(seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, lipoma).

Example liver cancers include, for example, hepatoma (hepatocellularcarcinoma), cholangiocarcinoma, hepatoblastoma, angio sarcoma,hepatocellular adenoma, and hemangioma.

Example bone cancers include, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant celltumors

Example nervous system cancers include, for example, cancers of theskull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans),meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastomamultiform, oligodendroglioma, schwannoma, retinoblastoma, congenitaltumors), and spinal cord (neurofibroma, meningioma, glioma, sarcoma), aswell as neuroblastoma and Lhermitte-Duclos disease.

Example gynecological cancers include, for example, cancers of theuterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumorcervical dysplasia), ovaries (ovarian carcinoma (serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), and fallopian tubes (carcinoma).

Example skin cancers include, for example, melanoma, basal cellcarcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplasticnevi, lipoma, angioma, dermatofibroma, and keloids.

The compounds of the invention can further be used to treat cancer typeswhere LSD1 may be overexpressed including, for example, breast,prostate, head and neck, laryngeal, oral, and thyroid cancers (e.g.,papillary thyroid carcinoma).

The compounds of the invention can further be used to treat geneticdisorders such as Cowden syndrome and Bannayan-Zonana syndrome.

The compounds of the invention can further be used to treat viraldiseases such as herpes simplex virus (HSV), varicella zoster virus(VZV), human cytomegalovirus, hepatitis B virus (HBV), and adenovirus.

The compounds of the invention can further be used to treatbeta-globinopathies including, for example, beta-thalassemia and sicklecell anemia.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” a LSD1 protein with a compound of the inventionincludes the administration of a compound of the present invention to anindividual or patient, such as a human, having a LSD1 protein, as wellas, for example, introducing a compound of the invention into a samplecontaining a cellular or purified preparation containing the LSD1protein.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician.

As used herein, the term “treating” or “treatment” refers to inhibitingthe disease; for example, inhibiting a disease, condition or disorder inan individual who is experiencing or displaying the pathology orsymptomatology of the disease, condition or disorder (i.e. arrestingfurther development of the pathology and/or symptomatology) orameliorating the disease; for example, ameliorating a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.reversing the pathology and/or symptomatology) such as decreasing theseverity of disease.

As used herein, the term “preventing” or “prevention” refers topreventing the disease; for example, preventing a disease, condition ordisorder in an individual who may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease.

Combination Therapies

The compounds of the invention can be used in combination treatmentswhere the compound of the invention is administered in conjunction withother treatments such as the administration of one or more additionaltherapeutic agents. The additional therapeutic agents are typicallythose which are normally used to treat the particular condition to betreated. The additional therapeutic agents can include, e.g.,chemotherapeutics, anti-inflammatory agents, steroids,immunosuppressants, as well as Bcr-Abl, Flt-3, RAF, FAK, JAK, PIM, PI3Kinhibitors for treatment of LSD1-mediated diseases, disorders orconditions. The one or more additional pharmaceutical agents can beadministered to a patient simultaneously or sequentially.

In some embodiments, the compounds of the invention can be used incombination with a therapeutic agent that targets an epigeneticregulator. Examples of epigenetic regulators include the histone lysinemethyltransferases, histone arginine methyl transferases, histonedemethylases, histone deacetylases, histone acetylases, and DNAmethyltransferases. Histone deacetylase inhibitors include, e.g.,vorinostat.

For treating cancer and other proliferative diseases, the compounds ofthe invention can be used in combination with chemotherapeutic agents,agonists or antagonists of nuclear receptors, or otheranti-proliferative agents. The compounds of the invention can also beused in combination with medical therapy such as surgery orradiotherapy, e.g., gamma-radiation, neutron beam radiotherapy, electronbeam radiotherapy, proton therapy, brachytherapy, and systemicradioactive isotopes. Examples of suitable chemotherapeutic agentsinclude any of: abarelix, aldesleukin, alemtuzumab, alitretinoin,allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase,azacitidine, bevacizumab, bexarotene, bleomycin, bortezombi, bortezomib,busulfan intravenous, busulfan oral, calusterone, capecitabine,carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine,clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin,dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin,denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolonepropionate, eculizumab, epirubicin, erlotinib, estramustine, etoposidephosphate, etoposide, exemestane, fentanyl citrate, filgrastim,floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib,gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelinacetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinibmesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate,lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole,lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine,methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone,nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin,paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine,quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib,streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide,teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan,toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard,valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, andzoledronate.

For treating cancer and other proliferative diseases, the compounds ofthe invention can be used in combination with ruxolitinib.

For treating autoimmune or inflammatory conditions, the compound of theinvention can be administered in combination with a corticosteroid suchas triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone,or flumetholone.

For treating autoimmune or inflammatory conditions, the compound of theinvention can be administered in combination with an immune suppressantsuch as fluocinolone acetonide (Retisert®), rimexolone (AL-2178, Vexol,Alcon), or cyclosporine (Restasis®).

For treating autoimmune or inflammatory conditions, the compound of theinvention can be administered in combination with one or more additionalagents selected from Dehydrex™ (Holles Labs), Civamide (Opko), sodiumhyaluronate (Vismed, Lantibio/TRB Chemedia), cyclosporine (ST-603,Sirion Therapeutics), ARG101(T) (testosterone, Argentis), AGR1012(P)(Argentis), ecabet sodium (Senju-Ista), gefarnate (Santen),15-(s)-hydroxyeicosatetraenoic acid (15(S)-HETE), cevilemine,doxycycline (ALTY-0501, Alacrity), minocycline, iDestrin™ (NP50301,Nascent Pharmaceuticals), cyclosporine A (Nova22007, Novagali),oxytetracycline (Duramycin, MOLI1901, Lantibio), CF101 (2S, 3S, 4R,5R)-3,4-dihydroxy-5-[6-[(3-iodophenyl)methylamino]purin-9-yl]-N-methyl-oxolane-2-carbamyl,Can-Fite Biopharma), voclosporin (LX212 or LX214, Lux Biosciences),ARG103 (Agentis), RX-10045 (synthetic resolvin analog, Resolvyx), DYN15(Dyanmis Therapeutics), rivoglitazone (DE011, Daiichi Sanko), TB4(RegeneRx), OPH-01 (Ophtalmis Monaco), PCS101 (Pericor Science), REV1-31(Evolutec), Lacritin (Senju), rebamipide (Otsuka-Novartis), OT-551(Othera), PAI-2 (University of Pennsylvania and Temple University),pilocarpine, tacrolimus, pimecrolimus (AMS981, Novartis), loteprednoletabonate, rituximab, diquafosol tetrasodium (INS365, Inspire), KLS-0611(Kissei Pharmaceuticals), dehydroepiandrosterone, anakinra, efalizumab,mycophenolate sodium, etanercept (Embrel®), hydroxychloroquine, NGX267(TorreyPines Therapeutics), or thalidomide.

For treating beta-thalassemia or sickle cell disease, the compound ofthe invention can be administered in combination with one or moreadditional agents such as Hydrea® (hydroxyurea).

In some embodiments, the compound of the invention can be administeredin combination with one or more agents selected from an antibiotic,antiviral, antifungal, anesthetic, anti-inflammatory agents includingsteroidal and non-steroidal anti-inflammatories, and anti-allergicagents. Examples of suitable medicaments include aminoglycosides such asamikacin, gentamycin, tobramycin, streptomycin, netilmycin, andkanamycin; fluoroquinolones such as ciprofloxacin, norfloxacin,ofloxacin, trovafloxacin, lomefloxacin, levofloxacin, and enoxacin;naphthyridine; sulfonamides; polymyxin; chloramphenicol; neomycin;paramomycin; colistimethate; bacitracin; vancomycin; tetracyclines;rifampin and its derivatives (“rifampins”); cycloserine; beta-lactams;cephalosporins; amphotericins; fluconazole; flucytosine; natamycin;miconazole; ketoconazole; corticosteroids; diclofenac; flurbiprofen;ketorolac; suprofen; cromolyn; lodoxamide; levocabastin; naphazoline;antazoline; pheniramine; or azalide antibiotic.

Other examples of agents, one or more of which a provided compound mayalso be combined with include: a treatment for Alzheimer's Disease suchas donepezil and rivastigmine; a treatment for Parkinson's Disease suchas L-DOPA/carbidopa, entacapone, ropinirole, pramipexole, bromocriptine,pergolide, trihexyphenidyl, and amantadine; an agent for treatingmultiple sclerosis (MS) such as beta interferon (e.g., Avonex® andRebif®), glatiramer acetate, and mitoxantrone; a treatment for asthmasuch as albuterol and montelukast; an agent for treating schizophreniasuch as zyprexa, risperdal, seroquel, and haloperidol; ananti-inflammatory agent such as a corticosteroid, such as dexamethasoneor prednisone, a TNF blocker, IL-1 RA, azathioprine, cyclophosphamide,and sulfasalazine; an immunomodulatory agent, includingimmunosuppressive agents, such as cyclosporin, tacrolimus, rapamycin,mycophenolate mofetil, an interferon, a corticosteroid,cyclophosphamide, azathioprine, and sulfasalazine; a neurotrophic factorsuch as an acetylcholinesterase inhibitor, an MAO inhibitor, aninterferon, an anti-convulsant, an ion channel blocker, riluzole, or ananti-Parkinson's agent; an agent for treating cardiovascular diseasesuch as a beta-blocker, an ACE inhibitor, a diuretic, a nitrate, acalcium channel blocker, or a statin; an agent for treating liverdisease such as a corticosteroid, cholestyramine, an interferon, and ananti-viral agent; an agent for treating blood disorders such as acorticosteroid, an anti-leukemic agent, or a growth factor; or an agentfor treating immunodeficiency disorders such as gamma globulin.

Formulation, Dosage Forms and Administration

When employed as pharmaceuticals, the compounds of the invention can beadministered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be, forexample, by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the invention or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers (excipients). In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the invention, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, for example, a capsule, sachet,paper, or other container. When the excipient serves as a diluent, itcan be a solid, semi-solid, or liquid material, which acts as a vehicle,carrier or medium for the active ingredient. Thus, the compositions canbe in the form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g., about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art, e.g., see International App. No.WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1,000 mg (1 g), more usually about 100mg to about 500 mg, of the active ingredient. The term “unit dosageforms” refers to physically discrete units suitable as unitary dosagesfor human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient.

The active compound may be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face masks tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, for example, liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, for example,glycerol, hydroxyethyl cellulose, and the like. In some embodiments,topical formulations contain at least about 0.1, at least about 0.25, atleast about 0.5, at least about 1, at least about 2, or at least about 5wt % of the compound of the invention. The topical formulations can besuitably packaged in tubes of, for example, 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention can varyaccording to, for example, the particular use for which the treatment ismade, the manner of administration of the compound, the health andcondition of the patient, and the judgment of the prescribing physician.The proportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

The compositions of the invention can further include one or moreadditional pharmaceutical agents such as a chemotherapeutic, steroid,anti-inflammatory compound, or immunosuppressant, examples of which arelisted hereinabove.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to labeled compounds ofthe invention (radio-labeled, fluorescent-labeled, etc.) that would beuseful not only in imaging techniques but also in assays, both in vitroand in vivo, for localizing and quantitating LSD1 in tissue samples,including human, and for identifying LSD1 ligands by inhibition bindingof a labeled compound. Accordingly, the present invention includes LSD1assays that contain such labeled compounds.

The present invention further includes isotopically-labeled compounds ofthe invention.

An “isotopically” or “radio-labeled” compound is a compound of theinvention where one or more atoms are replaced or substituted by an atomhaving an atomic mass or mass number different from the atomic mass ormass number typically found in nature (i.e., naturally occurring).Suitable radionuclides that may be incorporated in compounds of thepresent invention include but are not limited to ³H (also written as Tfor tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl,⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, 123I, ¹²⁴I, ¹²⁵I and ¹³¹I. The radionuclide thatis incorporated in the instant radio-labeled compounds will depend onthe specific application of that radio-labeled compound.

It is to be understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br. In some embodiments, the compoundincorporates 1, 2, or 3 deuterium atoms.

The present invention can further include synthetic methods forincorporating radio-isotopes into compounds of the invention. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of invention.

A labeled compound of the invention can be used in a screening assay toidentify/evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind LSD1 by monitoring its concentrationvariation when contacting with LSD1, through tracking of the labeling.For example, a test compound (labeled) can be evaluated for its abilityto reduce binding of another compound which is known to bind to LSD1(i.e., standard compound). Accordingly, the ability of a test compoundto compete with the standard compound for binding to LSD1 directlycorrelates to its binding affinity. Conversely, in some other screeningassays, the standard compound is labeled and test compounds areunlabeled. Accordingly, the concentration of the labeled standardcompound is monitored in order to evaluate the competition between thestandard compound and the test compound, and the relative bindingaffinity of the test compound is thus ascertained.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples were found to be inhibitorsof LSD1 as described below.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow. Preparatory LC-MS purifications of some of the compounds preparedwere performed on Waters mass directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature. See e.g.“Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K.Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification”, K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Hague, A. Combs, J. Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A.Combs, J. Combi. Chem., 6, 874-883 (2004). The compounds separated weretypically subjected to analytical liquid chromatography massspectrometry (LCMS) for purity check under the following conditions:Instrument; Agilent 1100 series, LC/MSD, Column: Waters Sunfire™ C₁₈ 5μm particle size, 2.1×5.0 mm, Buffers: mobile phase A: 0.025% TFA inwater and mobile phase B: acetonitrile; gradient 2% to 80% of B in 3minutes with flow rate 2.0 mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 μm particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.1% TFA (trifluoroacetic acid) inwater and mobile phase B: acetonitrile; the flow rate was 30 mL/minute,the separating gradient was optimized for each compound using theCompound Specific Method Optimization protocol as described in theliterature [see “Preparative LCMS Purification: Improved CompoundSpecific Method Optimization”, K. Blom, B. Glass, R. Sparks, A. Combs,J. Comb. Chem., 6, 874-883 (2004)]. Typically, the flow rate used withthe 30×100 mm column was 60 mL/minute.

pH=10 purifications: Waters)(Bridge C₁₈ 5 μm particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.15% NH₄OH in water and mobilephase B: acetonitrile; the flow rate was 30 mL/minute, the separatinggradient was optimized for each compound using the Compound SpecificMethod Optimization protocol as described in the literature [See“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)]. Typically, the flow rate used with 30×100 mm columnwas 60 mL/minute.

Example 14-{5-(4-methylphenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy][1,2,4]triazolo[1,5-a]pyridin-6-yl}benzonitrile

Step 1: 4-(6-amino-2-chloropyridin-3-yl)benzonitrile

A reaction vessel containing a mixture of5-bromo-6-chloropyridin-2-amine (415 mg, 2.00 mmol),(4-cyanophenyl)boronic acid (353 mg, 2.40 mmol),[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexedwith dichloromethane (1:1) (80 mg, 0.1 mmol) and potassium carbonate(550 mg, 4.0 mmol) in 1,4-dioxane (6 mL) and water (1 mL) was evacuatedthen refilled with nitrogen. The resulting mixture was heated to 80° C.and stirred for 3 h. The reaction mixture was cooled to room temperaturethen diluted with methylene chloride, washed with water, brine, driedover Na₂SO₄, filtered and concentrated. The residue was purified on asilica gel column eluting with 0 to 30% EtOAc/DCM to give the desiredproduct as a white solid (320 mg, 71%). LC-MS calculated for C₁₂H₉ClN₃(M+H)⁺: m/z=230.0; found 230.0.

Step 2: 4-[6-amino-2-(4-methylphenyl)pyridin-3-yl]benzonitrile

A reaction vessel containing a mixture of4-(6-amino-2-chloropyridin-3-yl)benzonitrile (320 mg, 1.39 mmol),4-methyl-8-(4-methylphenyl)-2,6-dioxotetrahydro[1,3,2]oxazaborolo[2,3-b][1,3,2]oxazaborol-4-ium-8-uide(413 mg, 1.67 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (60 mg, 0.07 mmol), and potassium carbonate(380 mg, 2.8 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was evacuatedthen filled with nitrogen. The resulting mixture was heated to 110° C.and stirred overnight. The mixture was cooled to room temperature thendiluted with methylene chloride, washed with saturated NaHCO₃ aqueoussolution, water, brine, dried over Na₂SO₄, filtered and concentrated.The residue was purified on a silica gel column eluting with 0 to 30%EtOAc/DCM to give the desired product as a light yellow solid (335 mg,84%). LC-MS calculated for C₁₉H₁₆N₃ (M+H)⁺: m/z=286.1; found 286.1.

Step 3: 4-[6-amino-5-bromo-2-(4-methylphenyl)pyridin-3-yl]benzonitrile

To a mixture of 4-[6-amino-2-(4-methylphenyl)pyridin-3-yl]benzonitrile(335 mg, 1.17 mmol) in tetrahydrofuran (5 mL) at 0° C. was added asolution of N-bromosuccinimide (230 mg, 1.3 mmol) in tetrahydrofuran (4mL). The resulting yellow solution was stirred at 0° C. for 1.5 h thendiluted with methylene chloride, washed with saturated NaHCO₃ aqueoussolution, water, brine, dried over Na₂SO₄, filtered and concentrated.The residue was purified on a silica gel column eluting with 0 to 30%EtOAc/DCM to give the desired product as a yellow solid (432 mg,quant.). LC-MS calculated for C₁₉H₁₅BrN₃ (M+H)⁺: m/z=364.0; found 364.0.

Step 4:N-[3-bromo-5-(4-cyanophenyl)-6-(4-methylphenyl)pyridin-2-yl]N′-hydroxyimidoformamide

To a mixture of4-[6-amino-5-bromo-2-(4-methylphenyl)pyridin-3-yl]benzonitrile (275 mg,0.755 mmol) in isopropyl alcohol (4 mL) was added1,1-dimethoxy-N,N-dimethylmethanamine (0.20 mL, 1.5 mmol). The mixturewas heated to 95° C. and stirred for 5 h. The resulting yellow solutionwas cooled to 50° C. then hydroxylamine hydrochloride (160 mg, 2.3 mmol)was added. The reaction mixture was stirred at 50° C. overnight thencooled to room temperature and concentrated. The residue was purified ona silica gel column eluting with 0 to 10% MeOH/DCM to give the desiredproduct as a yellow solid. LC-MS calculated for C₂H₁₆BrN₄O (M+H)⁺:m/z=407.1; found 407.0.

Step 5:4-[8-bromo-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile

To a solution ofN-[3-bromo-5-(4-cyanophenyl)-6-(4-methylphenyl)pyridin-2-yl]-N′-hydroxyimidoformamide(307 mg, 0.754 mmol) in tetrahydrofuran (5 mL) at 0° C. was addedtrifluoroacetic anhydride (180 μL, 1.2 mmol). The resulting yellowsolution was warmed to room temperature and stirred overnight. Thereaction was quenched with saturated NaHCO₃ aqueous solution thenextracted with methylene chloride. The combined extracts were washedwith water and brine. The organic layer was dried over Na₂SO₄ thenconcentrated. The residue was purified on a silica gel column elutingwith 0 to 20% EtOAc/DCM to give the desired product as a yellow solid.LC-MS calculated for C₂₀H₁₄BrN₄ (M+H)⁺: m/z=389.0; found 389.1.

Step 6:4-{5-(4-methylphenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy][1,2,4]triazolo[1,5-a]pyridin-6-yl}benzonitrile

A mixture of4-[8-bromo-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile(176 mg, 0.452 mmol), tert-butyl(3R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (182 mg, 0.904 mmol),π-allylpalladium chloride dimer (8 mg, 0.02 mmol),di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine(22 mg, 0.045 mmol) and cesium carbonate (221 mg, 0.678 mmol) in toluene(6 mL) was evacuated then filled with nitrogen. The resulting mixturewas heated to 110° C. and stirred overnight. The reaction mixture wascooled to room temperature then diluted with water and extracted withEtOAc. The combined extracts were washed with water and brine. Theorganic layer was dried over Na₂SO₄ then concentrated. The residue waspurified on a silica gel column eluted with 0 to 50% EtOAc/DCM to give ayellow solid, which was dissolved in methylene chloride (1.5 mL) thentrifluoroacetic acid (0.5 mL) was added. The resulting yellow solutionwas stirred at room temperature for 30 min then concentrated. Theresidue was dissolved in acetonitrile then purified by prep HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₅H₂₄N₅₀ (M+H)⁺: m/z=410.2; found 410.2.

Example 24-[5-(4-methylphenyl)-8-(2-pyrrolidin-3-ylethyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile

Step 1: tert-butyl 3-ethynylpyrrolidine-1-carboxylate

To a solution of tert-butyl 3-formylpyrrolidine-1-carboxylate (580 mg,2.91 mmol) in methanol (15 mL) at room temperature was added potassiumcarbonate (1.00 g, 7.28 mmol) and dimethyl(1-diazo-2-oxopropyl)phosphonate (839 mg, 4.37 mmol). The resultingmixture was stirred at room temperature for 3 h then passed through ashort pad of celite and concentrated. The residue was purified on asilica gel column eluting with 0 to 50% EtOAc/Hexanes to give theproduct as a colorless oil which solidified upon standing in fridge togive a white solid (374 mg, 66%).

Step 2: tert-butyl3-{[6-(4-cyanophenyl)-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-8-yl]ethynyl}pyrrolidine-1-carboxylate

A mixture of4-[8-bromo-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile(Example 1, Step 5, 70. mg, 0.18 mmol), tert-butyl3-ethynylpyrrolidine-1-carboxylate (53 mg, 0.27 mmol),tetrakis(triphenylphosphine)palladium(O) (21 mg, 0.018 mmol), andcopper(I) iodide (6.8 mg, 0.036 mmol) in N,N-dimethylformamide (2 mL)was evacuated then filled with nitrogen. Then N,N-diisopropylethylamine(94 μL, 0.54 mmol) was added. The resulting mixture was heated to 85° C.and stirred for 4 h. The reaction mixture was cooled to room temperaturethen diluted with EtOAc and washed with water and brine. The organiclayer was dried over Na₂SO₄ then concentrated. The residue was purifiedon a silica gel column eluting with 0 to 50% EtOAc/DCM to give thedesired product (62 mg, 68%). LC-MS calculated for C₃₁H₃₀N₅O₂ (M+H)⁺:m/z=504.2; found 504.2.

Step 3:4-[5-(4-methylphenyl)-8-(2-pyrrolidin-3-ylethyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile

To a solution of tert-butyl3-{[6-(4-cyanophenyl)-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-8-yl]ethynyl}pyrrolidine-1-carboxylate(62 mg, 0.12 mmol) in tetrahydrofuran (3 mL) and methanol (3 mL) wasadded palladium (10 wt % on activated carbon, 26 mg, 0.025 mmol). Theresulting mixture was stirred under a balloon of hydrogen overnight. Themixture was filtered through a short pad of celite then washed with THF.The filtrate was concentrated and the residue was dissolved in 3 mL ofDCM then 1 mL of TFA was added. The resulting yellow solution wasstirred at room temperature for 1 h then concentrated. The residue wasdissolved in acetonitrile then purified by prep HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₆H₂₆N₅ (M+H)⁺: m/z=408.2; found 408.2.

Example 34-{5-(4-methylphenyl)-8-[2-(1-methylpyrrolidin-3-yl)ethyl][1,2,4]triazolo[1,5-a]pyridin-6-yl}benzonitrile

To a solution of4-[5-(4-methylphenyl)-8-(2-pyrrolidin-3-ylethyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile(Example 2, Step 3, 14 mg, 0.034 mmol) in tetrahydrofuran (2 mL) wasadded formaldehyde (37 wt % in water, 13 μL, 0.17 mmol), followed byacetic acid (5.8 μL, 0.10 mmol). The resulting solution was stirred atroom temperature for 2 h, then sodium triacetoxyborohydride (22 mg, 0.10mmol) was added. The reaction mixture was stirred at room temperatureovernight then filtered and purified by prep HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₇H₂₈N₅ (M+H)⁺: m/z=422.2; found 422.3.

Example 44-[8-{3-[(methylamino)methyl]phenyl}-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile

Step 1:4-[8-(3-formylphenyl)-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile

A mixture of4-[8-bromo-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile(Example 1, Step 5, 53 mg, 0.14 mmol), (3-formylphenyl)boronic acid (41mg, 0.27 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (10 mg, 0.01 mmol), and potassium carbonate(38 mg, 0.27 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) wasevacuated then filled with nitrogen. The resulting mixture was heated to90° C. and stirred for 6 h. The reaction mixture was cooled to roomtemperature then diluted with DCM, filtered and concentrated. Theresidue was purified on a silica gel column eluting with 0 to 20%EtOAc/DCM to give the desired product as a yellow solid (45 mg, 80%).LC-MS calculated for C₂₇H₁₉N₄₀ (M+H)⁺: m/z=415.2; found 415.2.

Step 2:4-[8-{3-[(methylamino)methyl]phenyl}-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile

To a solution of4-[8-(3-formylphenyl)-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]henzonitrile(15 mg, 0.036 mmol) in tetrahydrofuran (2 mL) was added methylamine (2Min THF, 90. μL, 0.18 mmol), followed by acetic acid (10 μL, 0.18 mmol).The resulting mixture was stirred at room temperature for 2 h, thensodium triacetoxyborohydride (23 mg, 0.11 mmol) was added. The reactionmixture was stirred at room temperature overnight then diluted with THF,filtered and purified by prep HPLC (pH=2, acetonitrile/water+TFA) togive the desired product as the TFA salt. LC-MS calculated for C₂₈H24N₅(M+H)⁺: m/z=430.2; found 430.2.

Example 54-[8-{3-[(3-aminopyrrolidin-1-yl)methyl]phenyl}-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile

To a solution of4-[8-(3-formylphenyl)-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile(Example 4, Step 1, 15 mg, 0.036 mmol) in tetrahydrofuran (2 mL) wasadded tert-butyl pyrrolidin-3-ylcarbamate (20 mg, 0.11 mmol), followedby acetic acid (10. μL, 0.18 mmol). The resulting mixture was stirred atroom temperature for 2 h, then sodium triacetoxyborohydride (23 mg, 0.11mmol) was added. The reaction mixture was stirred at room temperatureovernight. The mixture was diluted with DCM then washed with saturatedNaHCO₃ aqueous solution. The organic layer was dried over Na₂SO₄ thenconcentrated. The residue was dissolved in methylene chloride (1 mL)then trifluoroacetic acid (1 mL) was added. The resulting yellowsolution was stirred at room temperature for 1 h then concentrated. Theresidue was dissolved in acetonitrile then purified by prep HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₃₁H₂₉N₆ (M+H)⁺: m/z=485.2; found 485.3.

Example 64-[5-(4-methylphenyl)-8-(piperazin-1-ylmethyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile

Step 1:4-[5-(4-methylphenyl)-8-vinyl[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile

A reaction vessel containing a mixture of4-[8-bromo-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]henzonitrile(Example 1, Step 5, 338 mg, 0.868 mmol),4-methyl-2,6-dioxo-8-vinyltetrahydro[1,3,2]oxazaborolo[2,3-b][1,3,2]oxazaborol-4-ium-8-uide(206 mg, 1.13 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (42 mg, 0.052 mmol), and potassium carbonate(240 mg, 1.7 mmol) in 1,4-dioxane (6 mL) and water (2 mL) was evacuatedthen filled with nitrogen. The resulting mixture was heated to 95° C.and stirred for 2 h. The mixture was cooled to room temperature thendiluted with methylene chloride, washed with saturated NaHCO₃ aqueoussolution, dried over Na₂SO₄, filtered and concentrated. The residue waspurified on a silica gel column eluting with 0 to 30% EtOAc/DCM to givethe desired product as a yellow solid (225 mg, 77%). LC-MS calculatedfor C₂₂H₁₇N₄ (M+H)⁺: m/z=337.1; found 337.1.

Step 2:4-[8-formyl-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile

To a solution of4-[5-(4-methylphenyl)-8-vinyl[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile(225 mg, 0.669 mmol) in 1,4-dioxane (10 mL) and water (3 mL) was addedosmium tetraoxide (4 wt % in water, 420 μL, 0.067 mmol). The resultingmixture was stirred at room temperature for 10 min then sodium periodate(429 mg, 2.01 mmol) was added. The reaction mixture was stirred at roomtemperature overnight. The reaction mixture was quenched with water thenextracted with DCM. The combined extracts were washed with water andbrine then dried over Na₂SO₄ and concentrated. The residue was purifiedon a silica gel column eluting with 0 to 30% EtOAc/DCM to give thedesired product as a yellow solid (159 mg, 70%). LC-MS calculated forC₂₁H₁₅N₄O (M+H)⁺: m/z=339.1; found 339.2.

Step 3:4-[5-(4-methylphenyl)-8-(piperazin-1-ylmethyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile

To a solution of4-[8-formyl-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile(14 mg, 0.041 mmol) in methylene chloride (2 mL) was added tert-butylpiperazine-1-carboxylate (23 mg, 0.12 mmol), followed by acetic acid (12μL, 0.21 mmol). The resulting mixture was stirred at room temperatureovernight then sodium triacetoxyborohydride (26 mg, 0.12 mmol) wasadded. The reaction mixture was stirred at room temperature for 2 h thendiluted with DCM and washed with saturated NaHCO₃ aqueous solution. Theorganic layer was dried over Na₂SO₄ then concentrated. The residue wasdissolved in methylene chloride (1 mL) then trifluoroacetic acid (1 mL)was added. The resulting yellow solution was stirred at room temperaturefor 1 h then concentrated. The residue was dissolved in acetonitrilethen purified by prep HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as the TFA salt. LC-MS calculated for C₂₅H₂₅N₆ (M+H)⁺:m/z=409.2; found 409.2.

Example 74-{5-(4-methylphenyl)-8-[(4-methylpiperazin-1-yl)methyl][1,2,4]triazolo[1,5-a]pyridin-6-yl}benzonitrile

To a solution of4-[8-formyl-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile(Example 6, Step 2, 14 mg, 0.041 mmol) in methylene chloride (2 mL) wasadded 1-methyl-piperazine (14 μL, 0. 12 mmol), followed by acetic acid(12 μL, 0.21 mmol). The resulting mixture was stirred at roomtemperature overnight then sodium triacetoxyborohydride (26 mg, 0.12mmol) was added. The reaction mixture was stirred at room temperaturefor 2 h then diluted with DCM and washed with saturated NaHCO₃ aqueoussolution. The organic layer was dried over Na₂SO₄ then concentrated. Theresidue was dissolved in acetonitrile then purified by prep HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₆H₂₇N₆ (M+H)⁺: m/z=423.2; found 423.3.

Example 84-[8-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]methyl}-5-(4-methylphenyl)[1,2,4]triazolo-pyridin-6-yl]benzonitrile

To a solution of4-[8-formyl-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile(Example 6, Step 2, 57 mg, 0.17 mmol) in methylene chloride (3.0 mL) wasadded (3S)—N,N-dimethylpyrrolidin-3-amine (TCI, Cat#D2193: 64 μL, 0.50mmol), followed by acetic acid (28 μL, 0.50 mmol). The resulting mixturewas stirred at room temperature for 1 h, then sodiumtriacetoxyborohydride (71 mg, 0.34 mmol) was added. The reaction mixturewas stirred at room temperature for 2 h then diluted with DCM and washedwith saturated NaHCO₃ aqueous solution. The organic layer was dried overNa₂SO₄ then concentrated. The residue was dissolved in acetonitrile thenpurified by prep HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as the TFA salt. LCMS calculated for C₂₇H29N₆ (M+H)⁺: m/z=437.2;Found: 437.2. ¹H NMR (500 MHz, DMSO) δ 8.53 (s, 1H), 7.86 (s, 1H), 7.79(d, J=8.3 Hz, 2H), 7.41 (d, J=8.3 Hz, 2H), 7.28 (d, J=8.1 Hz, 2H), 7.22(d, J=8.1 Hz, 2H), 4.49 (s, 2H), 3.97 (br, 1H), 3.38 (br, 2H), 3.27 (br,1H), 3.09 (br, 1H), 2.78 (s, 6H), 2.33 (s, 3H), 2.29 (br, 1H), 2.19 2.08(m, 1H).

Example 94-[8-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]methyl}-5-(4-methylphenyl)[1,2,4]triazolo-[1,5-a]pyridin-6-yl]benzonitrile

This compound was prepared using procedures analogous to those describedfor Example 8 with (3R)—N,N-dimethylpyrrolidin-3-amine replacing(3S)—N,N-dimethylpyrrolidin-3-amine.

The compound was purified by prep HPLC (pH=2, acetonitrile/water+TFA) togive the desired product as the TFA salt. LCMS calculated for C₂₇H₂₉N₆(M+H)⁺: m/z=437.2; Found: 436.7.

Example 104-[8-{[(3S)-3-(methylamino)pyrrolidin-1-yl]methyl}-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile

To a solution of4-[8-formyl-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile(Example 6, Step 2, 6.0 mg, 0.018 mmol) in methylene chloride (1.0 mL)was added tert-butyl methyl[(3S)-pyrrolidin-3-yl]carbamate (18 mg, 0.089mmol), followed by acetic acid (10 μL, 0.18 mmol). The resulting mixturewas stirred at room temperature overnight, then sodiumtriacetoxyborohydride (11 mg, 0.053 mmol) was added. The reactionmixture was stirred at room temperature for 2 h then diluted with DCMand washed with saturated NaHCO₃ aqueous solution. The organic layer wasdried over Na₂SO₄ then concentrated. The residue was dissolved inmethylene chloride (1 mL) then trifluoroacetic acid (0.5 mL) was added.The resulting yellow solution was stirred at room temperature for 2 hthen concentrated. The residue was dissolved in acetonitrile thenpurified by prep HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as the TFA salt. LCMS calculated for C₂₆H₂₇N₆ (M+H)⁺: m/z=423.2;Found: 423.2.

Example 11

4-[8-{[(3R)-3-(methylamino)pyrrolidin-1-yl]methyl}-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile

This compound was prepared using procedures analogous to those describedfor Example 10 with tert-butyl methyl[(3R)-pyrrolidin-3-yl]carbamatereplacing tert-butyl methyl[(3S)-pyrrolidin-3-yl]carbamate. The compoundwas purified by prep HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as the TFA salt. LCMS calculated for C₂₆H₂₇N₆ (M+14)⁺:m/z=423.2; Found: 423.1.

Example 124-{5-(4-methylphenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy][1,2,4]triazolo[1,5-a]pyrazin-6-yl}benzonitrile

Step 1: 4-(5-amino-3-chloropyrazin-2-yl)benzonitrile

A mixture of 5-bromo-6-chloropyrazin-2-amine (1.04 g, 5.00 mmol),(4-cyanophenyl)boronic acid (0.882 g, 6.00 mmol),dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl}Vanadium(110 mg, 0.15 mmol), sodium carbonate (1.06 g, 10.0 mmol) in 1,4-dioxane(12.0 mL) and water (2.0 mL) was evacuated then filled with nitrogen.The resulting mixture was stirred at 90° C. for 4 h then cooled to roomtemperature. The mixture was diluted with methylene chloride (15 mL) andwater (5 mL). The precipitates were collected by filtration and washedwith methyl t-butyl ether then dried to afford the desired product (1.05g, 91%). LC-MS calculated for C₁₁H₈ClN₄ (M+H)⁺: m/z=231.0; found 231.1.

Step 2: 4-[5-amino-3-(4-methylphenyl)pyrazin-2-yl]benzonitrile

A reaction vessel containing a mixture of4-(5-amino-3-chloropyrazin-2-yl)benzonitrile (1.15 g, 5.00 mmol),(4-methylphenyl)boronic acid (0.86 g, 6.4 mmol), sodium carbonate (1.06g, 10.0 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(H) complexedwith dichloromethane (1:1) (0.20 g, 0.25 mmol) in 1,4-dioxane (20.0 mL)and water (4.0 mL) was evacuated then refilled with nitrogen. Theresulting mixture was stirred at 110° C. for 3 h then cooled to roomtemperature. The mixture was diluted with methylene chloride, washedwith saturated NaHCO₃ aqueous solution, water and brine. The organiclayer was dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was treated with DCM/diethyl-ether (1:1). Theprecipitate was collected by filtration to afford the desired product(0.61 g). The filtrate was concentrated and the residue was purified byflash chromatography on a silica gel column eluting with 0 to 100%EtOAc/DCM to afford another batch of the product (0.60 g). LC-MScalculated for C₁₈H₁₅N₄ (M+H)⁺: m/z=287.1; found 287.1.

Step 3: 4-[5-amino-6-bromo-3-(4-methylphenyl)pyrazin-2-yl]benzonitrile

To a solution of 4-[5-amino-3-(4-methylphenyl)pyrazin-2-yl]benzonitrile(2.40 g, 8.38 mmol) in tetrahydrofuran (36 mL) at 0° C. was addedN-bromosuccinimide (1.64 g, 9.22 mmol). The resulting mixture wasstirred at 0° C. for 1 h then warmed to room temperature. The mixturewas diluted with methylene chloride, washed with saturated NaHCO₃aqueous solution, water, and brine. The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was purified on a silicagel column eluting with 0 to 60% EtOAc/DCM to give the desired product(2.8 g, 92%). LC-MS calculated for C₁₈H₁₄BrN₄ (M+H)⁺: m/z=365.0; found365.0.

Step 4: tert-butyl(3R)-3-({[3-amino-6-(4-cyanophenyl)-5-(4-methylphenyl)pyrazin-2-yl]oxy}methyl)pyrrolidine-1-carboxylate

To a solution of tert-butyl(3R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (2.06 g, 10.2 mmol) intetrahydrofuran (25 mL) at room temperature was added NaH (60 wt. % inmineral oil, 413 mg, 17.2 mmol). The resulting mixture was stirred atroom temperature for 30 min then4-[5-amino-6-bromo-3-(4-methylphenyl)pyrazin-2-yl]benzonitrile (1.50 g,4.10 mmol) was added. The reaction mixture was stirred at 85° C. for 15h then cooled to room temperature. The mixture was quenched withsaturated NaHCO₃ aqueous solution and extracted with EtOAc. The combinedorganic layers were dried over Na₂SO₄, and concentrated. The residue waspurified on a silica gel column eluting with 10 to 40% EtOAc/DCM to givethe product as a yellow solid. LC-MS calculated for C₂₄H₂₄N₅O₃(M-tBu+2H)⁺: m/z=430.2; found 430.1.

Step 5:4-{5-(4-methylphenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy][1,2,4]triazolo[1,5-a]pyrazin-6-yl}benzonitrile

A mixture of tert-butyl(3R)-3-({[3-amino-6-(4-cyanophenyl)-5-(4-methylphenyl)pyrazin-2-yl]oxy}methyl)pyrrolidine-1-carboxylate(100 mg, 0.2 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (137 μL,1.03 mmol) in isopropyl alcohol (1.5 mL) was heated to 95° C. andstirred for 2 h. The reaction mixture was cooled to room temperaturethen concentrated. The residue was dissolved in methanol (1.5 mL) andcooled to 0° C. then pyridine (50. μL, 0.62 mmol) was added, followed byhydroxylamine-O-sulfonic acid (58 mg, 0.51 mmol). The reaction mixturewas warmed to room temperature and stirred overnight. The mixture wasthen quenched with saturated NaHCO₃ solution and extracted with EtOAc.The combined extracts were dried over Na₂SO₄ and then concentrated. Theresidue was purified on a silica gel column to give the desiredintermediate, which was then dissolved in methylene chloride (1.5 mL)and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred atroom temperature for 1 h and then concentrated. The crude material wasthen purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as the TFA salt. LC-MS calculated for C₂₄H₂₃N₆₀ (M+H)⁺:m/z=411.2; found 411.2. ¹H NMR (500 MHz, DMSO) δ 8.86 (br, 2H), 8.61 (s,1H), 7.80-7.72 (m, 2H), 7.57-7.51 (m, 2H), 7.31 (d, J=8.1 Hz, 2H), 7.26(d, J=8.1 Hz, 2H), 4.69-4.56 (m, 2H), 3.48-3.38 (m, 1H), 3.38-3.18 (m,2H), 3.16-3.06 (m, 1H), 2.98-2.87 (m, 1H), 2.35 (s, 3H), 2.22-2.12 (m,1H), 1.91-1.80 (m, 1H).

Example 134-(5-(4-methylphenyl)-8-{[(3R)-1-methylpyrrolidin-3-yl]methoxy}[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of4-{5-(4-methylphenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy][1,2,4]triazolo[1,5-a]pyrazin-6-yl}benzonitrile(Example 12: 10 mg, 0.02 mmol) in methylene chloride (1.5 mL) was addedformaldehyde (37 wt. % in water, 18.1 μL, 0.244 mmol), followed byacetic acid (6.9 μL, 0.12 mmol). The resulting mixture was stirred atroom temperature for 3 h then sodium triacetoxyborohydride (26 mg, 0.12mmol) was added. The reaction mixture was stirred at room temperaturefor another 2 h then concentrated. The resulting residue was thenpurified by prep HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as the TFA salt. LC-MS calculated for C₂₅H₂₅N₆₀ (M+H)⁺:m/z=425.2; found 425.2.

Example A: LSD1 Histone Demethylase Biochemical Assay

LANCE LSD1/KDM1A demethylase assay—10 μL of 1 nM LSD-1 enzyme (ENZOBML-SE544-0050) in the assay buffer (50 mM Tris, pH 7.5, 0.01% Tween-20,25 mM NaCl, 5 mM DTT) were preincubated for 1 hour at 25° C. with 0.8 μLcompound/DMSO dotted in black 384 well polystyrene plates. Reactionswere started by addition of 10 μL of assay buffer containing 0.4 μMBiotin-labeled Histone H₃ peptide substrate:ART-K(Me1)-QTARKSTGGKAPRKQLA-GGK(Biotin) SEQ ID NO:1 (AnaSpec 64355) andincubated for 1 hour at 25° C. Reactions were stopped by addition of 10μL 1×LANCE Detection Buffer (PerkinElmer CR97-100) supplemented with 1.5nM Eu-anti-unmodified H3K4 Antibody (PerkinElmer TRF0404), and 225 nMLANCE Ultra Streptavidin (PerkinElmer TRF102) along with 0.9 mMTranylcypromine-HCl (Millipore 616431). After stopping the reactionsplates were incubated for 30 minutes and read on a PHERAstar FS platereader (BMG Labtech). IC₅₀ data for the example compounds is provided inTable 1 (+refers to IC₅₀≤50 nM; ++ refers to IC₅₀>50 nM and ≤100 nM; +++refers to IC₅₀>50 nM and <100 nM; ++++ refers to IC₅₀>500 nM and ≤1000nM).

TABLE 1 Example No. IC₅₀ (nM) 1 + 2 + 3 ++ 4 +++ 5 ++ 6 +++ 7 +++ 8 + 9++ 10 + 11 + 12 + 13 +++

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

What is claimed is:
 1. A compound of Formula IIa:

or a pharmaceutically acceptable salt thereof, wherein: Ring A isphenyl, substituted with CN; Ring B is C₆₋₁₀ aryl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl, or 4-10 membered heterocycloalkyl, whereinthe C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, and 4-10membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 independently selected R^(B) substituents, and further wherein the4-10 membered heterocycloalkyl and the 5-10 membered heteroarylindependently comprise carbon and 1, 2, 3, or 4 heteroatomsindependently selected from the group consisting of nitrogen, oxygen,and sulfur, and further wherein the carbon or heteroatoms of the 4-10membered heterocycloalkyl may be oxidized to form a carbonyl group orsulfonyl group; R¹ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, Cy¹, OR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), S(O)₂R^(b1), orS(O)₂NR^(c1)R^(d1); wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of Cy¹, halo, CN,OR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1); R² is H, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, or Cy², whereinthe C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of Cy², halo, CN, and OR^(a2); each R^(B) isindependently selected from the group consisting of halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, and OR^(a5); each Cy¹ isindependently selected from the group consisting of C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl, each of which is optionally substituted with 1, 2, 3,or 4 independently selected R^(Cy) substituents; each Cy² isindependently selected from the group consisting of C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl, each of which is optionally substituted with 1, 2, 3,or 4 independently selected R^(Cy) substituents; each Cy⁴ isindependently selected from the group consisting of C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl, each of which is optionally substituted with 1, 2, 3,or 4 independently selected R^(Cy) substituents; each R^(Cy) isindependently selected from the group consisting of halo, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl,C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₄ alkyl-, C₃₋₇ cycloalkyl-C₁₋₄ alkyl-, (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₄alkyl-, CN, NO₂, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6), C(═NR^(e6)NR^(c6)R^(d6),R^(c6)C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)OR^(a6), NR^(c6)C(O)NR^(c6)R^(d6) NR^(c6)S)R^(b6),NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6), wherein the C₁₋₄alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₄ alkyl-, C₃₋₇cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, and (4-7membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionally substitutedwith 1, 2, or 3 substituents independently selected from the groupconsisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN,NO₂, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6) NR^(c6)R^(d6) NR^(c6)C(O)R^(b6),NR^(c6)C(O)OR^(a6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)S(O)R^(b6),NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6); each R^(a1) isindependently selected from the group consisting of H, C₁₋₆ alkyl, and4-7 membered heterocycloalkyl, wherein the C₁₋₆ alkyl is optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of Cy⁴, halo, CN, OR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3), and wherein the 4-7 memberedheterocycloalkyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halo, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂, OR^(a6), C(O)R^(b6),C(O)NR^(c6)R^(d6), C(O)OR^(a6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6); each R^(b1), R^(c1), and R^(d1) isindependently selected from the group consisting of H, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted with 1, 2,3, 4, or 5 substituents independently selected from the group consistingof C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a7),SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7),OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7); each R^(a2) is independently selected from the groupconsisting of H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom the group consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄cyanoalkyl, halo, CN, OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7),C(O)OR^(a7), OC(O)R^(b7), OC(O)NR^(c7)R^(d7) NR^(c7)R^(d7)NR^(c7)C(O)R^(b7) NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7),C(═NR^(e7))NR^(c7)R^(d7), NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), S(O)R^(b7),S(O)NR^(c7)R^(d7), S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7),NR^(c7)S(O)₂NR^(c7)R^(d7), and S(O)₂NR^(c7)R^(d7); each R^(a3), R^(b3),R^(c3), and R^(d3) is independently selected from the group consistingof H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom the group consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄cyanoalkyl, halo, CN, OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7),C(O)OR^(a7), OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7),NR^(c7)C(O)R^(b7), NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7),C(═NR^(e7))NR^(c7)R^(d7), NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), S(O)R^(b7),S(O)NR^(c7)R^(d7), S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7),NR^(c7)S(O)₂NR^(c7)R^(d7), and S(O)₂NR^(c7)R^(d7); each R^(a5) isindependently selected from the group consisting of H, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted with 1, 2,3, 4, or 5 substituents independently selected from the group consistingof C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a7),SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7),OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(C7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7); each R^(a6), R^(b6), R⁶, and R^(d6) is independentlyselected from the group consisting of H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a7), SR^(a7),C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7),OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), S(O)R^(b7) S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7) andS(O)₂NR^(c7)R^(d7); each R^(a7), R^(b7), R^(c7), and R^(d7) isindependently selected from the group consisting of H, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl, C₂₋₄alkenyl, and C₂₋₄ alkynyl are each optionally substituted with 1, 2, or3 substituents independently selected from the group consisting of OH,CN, amino, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;and each R^(e6) and R^(c7) is independently selected from H, C₁₋₄ alkyl,and CN.
 2. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein Ring B is phenyl or 5-6 membered heteroaryl,wherein the phenyl and 5-6 membered heteroaryl are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(B)substituents.
 3. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein Ring B is phenyl, wherein the phenyl isoptionally substituted with 1 or 2 independently selected R^(B)substituents.
 4. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein Ring B is phenyl, wherein the phenyl issubstituted with one R^(B) substituent.
 5. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein Ring B is phenyl,wherein the phenyl is substituted with one methyl substituent.
 6. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein each R^(B) is an independently selected C₁₋₆ alkyl substituent.7. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R¹ is C₁₋₆ alkyl, Cy¹, or OR^(a1), wherein the C₁₋₆alkyl is substituted with one Cy¹ substituent.
 8. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein each Cy¹ isindependently phenyl or 4-7 membered heterocycloalkyl, wherein thephenyl and 4-7 membered heterocycloalkyl are each optionally substitutedwith 1 or 2 independently selected R^(Cy) substituents.
 9. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein eachR^(Cy) is independently C₁₋₄ alkyl or NR^(c6)R^(d6), wherein the C₁₋₄alkyl is optionally substituted with one NR^(c6)R^(d6) substituent. 10.A pharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier.